Folate And Vitamin D ~ Rubye Top Nutrition

Folate And Vitamin D

INTRODUCTION

The vitamin D-folate hypothesis is a prevailing theory that explains the evolution of human skin coloration, postulating that changes in skin pigmentation occurred as an evolutionary adaptation to geographical variations in ultraviolet radiation (UVR) exposure (35, 36). Early humans inhabiting equatorial Africa are purported to have adopted a darkened skin pigment as protection from photodegradation of the bioactive metabolite of folate, 5-methyltetrahydrofolate (5-MTHF). 5-MTHF is important for promoting healthy pregnancy and childbirth (63), and its evolutionary preservation would therefore enhance reproductive viability. As humans migrated away from the equator, however, depigmentation likely occurred to allow for adequate biosynthesis of previtamin D₃ upon UVR exposure, which is likewise of evolutionary significance due to the importance of vitamin D in pregnant and lactating women and development of the skeletal system during early childhood (37). However, differences in human skin pigmentation may result in susceptibility to photodegradation of 5-MTHF for those with light skin pigments in UVR-rich environments, or inadequate vitamin D₃ synthesis for those with darker pigments in environments of low UVR exposure or high seasonal variation.

In addition to the importance of 5-MTHF and vitamin D in healthy pregnancy and child development, recent evidence has emerged that both 5-MTHF (87) and vitamin D (60) play important roles in vascular health. Vascular endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key pathological antecedent to the development of cardiovascular disease. Both 5-MTHF and vitamin D directly and indirectly regulate NO bioavailability, and as such, both are important in maintaining healthy endothelial function (66) and protecting against the development of cardiovascular disease (12, 55). UVR exposure may have either deleterious or beneficial effects on vascular function, and those disparate effects may be modulated through either 5-MTHF or vitamin D metabolism. These effects of UVR likely differ based on factors such as UVR wavelength, dose, and individual variation in human characteristics, including skin pigmentation, genetics, and age. The purpose of this review is to examine the potential influences of UVR on vascular health via its differential effects on 5-MTHF and vitamin D metabolism, and the role of skin pigmentation and other biological variants in modulating these effects.

DIFFERENTIAL VASCULAR EFFECTS ACROSS THE ULTRAVIOLET SPECTRUM

The UVR spectrum from sunlight is categorized into three primary regions; UV-A (320–400 nm), UV-B (290–320 nm), and UV-C (200–290 nm), and the biological effects of UVR differ by wavelength (18). UV-C is not considered biologically relevant, because it is filtered by the ozone layer and does not reach the surface of the earth (21). UV-A constitutes ~95% of UVR that reaches the earth's surface, with the remaining 5% comprising UV-B (5). In the skin, UV-A is able to penetrate the dermis and reach the cutaneous circulation, whereas UV-B is mostly absorbed in the epidermis and upper dermis due to its shorter wavelengths. As such, UV-A and UV-B elicit their respective biological effects via distinct direct and indirect mechanisms.

Although UV-B constitutes only a small percentage of the total UVR that reaches the skin and its ability to directly affect the cutaneous circulation is limited, it is highly energetic and biologically impactful. Indeed, the minimal erythema dose (the minimal dose required to elicit a reddening response in the skin) is 1,000-fold less for UV-B than UV-A radiation (67). Exposure of human skin keratinocytes to UV-B results in production of reactive oxygen species (ROS) (6, 21, 86), which may be responsible for multiple deleterious effects of UVR including carcinogenesis and skin aging (62). Conversely, UV-B also interacts with 7-dehydrocholesterol (7-DHC) stores in the skin to produce vitamin D (30), which may have vascular health benefits (discussed in more detail in a subsequent section of this review). UV-A is less energetic than UV-B but penetrates deeper into the skin (21). ROS may be produced by UV-A exposure either in the skin or in the dermal circulation via interaction with skin chromophores or circulating photosensitizers such as uroporphyrin or riboflavin (53, 73). UV-A may also elicit some beneficial vascular effects via photolysis of cutaneous nitrites to NO (50, 58) (discussed further in a later section of this review). Thus, UV-A and UV-B exposure may differentially influence vascular function and health through distinct but interrelated mechanisms (Fig. 1).

**Fig. 1.**Putative mechanistic pathways by which ultraviolet radiation (UVR) exposure may influence nitric oxide (NO) bioavailability and vascular function. Deleterious and beneficial pathways are represented by dotted and solid lines, respectively. Ultraviolet-A (UV-A) and/or B (UV-B) exposure to the skin may reduce 5-methyltetrahydrofolate (5-MTHF) bioavailability, thereby reducing NO production and blunting NO-mediated vasodilation. UV-B is absorbed by 7-dehydrocholesterol (7-DHC) stores in the skin, resulting in formation of previtamin D₃, which is rapidly converted to vitamin D₃. Vitamin D₃ undergoes two hydroxylation steps, first producing 25-hydroxyvitamin D [25(OH)D] in the liver and then producing 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃]. 1,25-(OH)₂D₃ binds to vitamin D receptors (VDRs), signaling for transcription of endothelial NO synthase (eNOS) and superoxide dismutase (SOD), thereby increasing NO bioavailability and augmenting NO-mediated vasodilation.

ULTRAVIOLET RADIATION, VITAMIN D METABOLISM, AND VASCULAR FUNCTION

The association between vitamin D metabolism and sunlight, or UVR exposure, is well known. Approximately 90% of the human vitamin D requirement [serum 25(OH)D concentration 30–60 ng/ml] is met via skin exposure to sunlight (29, 30, 59). Mechanistically, UV-B is absorbed by epidermal and dermal stores of 7-dehydrocholesterol (7-DHC), resulting in formation of previtamin D₃, which is then rapidly converted to vitamin D₃. Subsequently, vitamin D₃ undergoes two hydroxylation steps. The first hydroxylation step forms 25-hydroxyvitamin D [25(OH)D] and is catalyzed within the liver by 25-hydroxylase. The second step forms the predominant biologically active vitamin D metabolite 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] and is catalyzed in the kidney by 1α-hydroxylase. An independent, local vitamin D metabolism pathway for synthesis of 1,25(OH)₂D₃ is found in human skin (48, 65), where it may serve paracrine or autocrine functions. The vitamin D receptor (VDR), found in most human cells, is a transcription factor that controls gene expression for a multitude of tissue-specific responses upon binding with 1,25(OH)₂D₃. Although it is most recognized for its role in bone and mineral homeostasis, the VDR serves many physiological functions that may include beneficial effects on vascular function and health (9).

Determinants of Vitamin D Status

An individual's vitamin D status is influenced by a number of exogenous and endogenous factors.

UV exposure.

UV-B exposure varies geographically and seasonally, such that exposure is diminished with increasing distance from the Earth's equator and during the winter months, particularly in areas of greater seasonal variation (59). Significant variation was observed in vitamin D status between summer and winter months in Boston, with 30% of study participants being vitamin D insufficient at the end of winter compared with only 11% at the end of summer (74). Sufficient production of vitamin D is additionally impacted by lifestyle, including time spent outdoors. Wearing a sunscreen with sun protection factor (SPF) of 30 or higher reduces skin vitamin D synthesis by more than 95% and therefore may prevent adequate vitamin D status in at-risk populations (31).

Age.

Aging may substantially reduce the skin's ability to produce vitamin D₃ due to a linear age-related decline in epidermal 7-DHC bioavailability after the age of 20 yr (52). Adequate vitamin D status can likely be maintained in older adults with regular sun exposure to large areas of the skin (16); otherwise the aged population is at greater risk of insufficient previtamin D₃ production. Furthermore, reduced glomerular filtration rates in the aged kidney may result in attenuated renal hydroxylation of 25(OH)D to 1,25(OH)₂D₃ (77). Therefore, vitamin D supplementation may be warranted in adults over the age of 60 yr to maintain sufficient circulating 25(OH)D concentrations and 1,25(OH)₂D₃ activity (17).

Skin pigmentation.

Melanin within the skin absorbs UV-B radiation, preventing its absorption by cutaneous 7-DHC, and thereby reducing vitamin D₃ biosynthesis (14). Those with greater skin melanization, characterized by a darkened pigmentation, are at a particularly high risk for vitamin D deficiency, especially those living in areas of low UVR exposure or high seasonal variation. In a large cohort of 2,097 darkly pigmented African-American and 1,860 lightly pigmented Euro-American women of reproductive age, 41% of African-American women were vitamin D deficient at the end of summer compared with only 4% of Euro-American women (56).

Genetics.

Although skin pigmentation is predictive for circulating vitamin D concentration, genes related to vitamin D metabolism also play an important role in UV-B-induced vitamin D production (15, 81). Single-nucleotide polymorphisms of four pigment-related genes (ASIP, SLC24A4, SLC45A2, and MIR196A29) explain more of the variation in UV-B-induced vitamin D production than skin pigment per se (15), suggesting that genes related to skin pigmentation have a role in other physiological processes, including vitamin D metabolism, although the mechanisms are currently unclear. Two genomewide association studies identified single-nucleotide polymorphisms associated with 25(OH)D concentrations at three loci; GC (vitamin D binding protein), DHCR7 (7-DHC reductase), and CYP2R1 (25-hydroxylase) (1, 81). Polymorphisms in GC and CYP2R1 are characterized by alterations in vitamin D binding protein phenotypes (89) and activity of the hepatic enzyme 25-hydroxylase (13), respectively, and therefore may result in variations in vitamin D homeostasis. 7-DHC reductase catalyzes the conversion of 7-DHC to cholesterol, thereby reducing availability of the vitamin D₃ precursor. Thus, variations in DHCR7 may confer benefits for vitamin D production by conserving cutaneous 7-DHC concentrations. High prevalence of DHCR7 variants related to reduced 7-DHC reductase activity were demonstrated in European and Northeast Asian populations, but not in African populations, suggesting that selection occurred for these DHCR7 mutations in populations who migrated away from the equator to more northern latitudes (43).

Vitamin D and Vascular Health

Associations between vitamin D status and hypertension (42), cardiovascular disease (80), and vascular function (2) have been well documented. Adrukhova et al. (4) demonstrated that 1,25(OH)₂D₃ is a direct transcriptional regulator of endothelial nitric oxide synthase (eNOS), and that mice carrying a functionally inactive, mutant VDR were characterized by increased arterial stiffness and reduced eNOS expression and NO bioavailability. Additionally, serum concentrations of 25(OH)D, the primary circulating vitamin D metabolite, were directly related to brachial artery flow-mediated dilation (FMD) in otherwise healthy middle-aged and older adults (34). That study further demonstrated that serum concentrations of 25(OH)D were inversely related to vascular endothelial cell expression of interleukin-6 (IL-6) and that suppression of nuclear factor-κB (NF-κB) improved FMD to a greater extent in those with lower compared with higher 25(OH)D status. Finally, 25(OH)D-deficient subjects exhibited lower endothelial cell expression of VDR and of 1α-hydroxylase, the enzyme responsible for conversion of 25(OH)D to 1,25(OH)₂D₃. Taken together, these studies suggest important roles for vitamin D in vascular health acting mechanistically to preserve production of NO and suppress inflammation-induced vascular dysfunction.

Data from the National Health and Nutrition Examination Survey (NHANES) demonstrated a high prevalence of vitamin D insufficiency in individuals with a variety of cardiovascular diseases (CVDs) including coronary heart disease, heart failure, stroke, and peripheral arterial disease (40). Importantly, a higher prevalence of hypovitaminosis D was observed in African-American (97%) compared with Euro-American (77%) subjects in that survey. These epidemiological data suggest a potential causal link between vitamin D insufficiency and impaired cardiovascular health, which may be reflected in the disproportionate CVD burden in the African-American population (7).

Hypertension, a leading risk factor for CVD, develops at a younger age and contributes disproportionately to increased mortality in African-Americans (7). Attenuated conduit artery (11) and microvascular (33, 41) function, both of which are implicated in the development of hypertension (25, 57), are observed in otherwise healthy African-American compared with Euro-American subjects. Brothers and colleagues (33, 41) demonstrated impairments in NO-mediated vasodilation of the cutaneous microvasculature in response to local heating in healthy, college-aged African-Americans compared with their Euro-American counterparts. Furthermore, when tempol [a superoxide dismutase (SOD) mimetic] was locally delivered via intradermal microdialysis, NO-mediated vasodilation was normalized in the African-American subjects such that there were no longer differences between groups (33). Thus, microvascular dysfunction observed in African-Americans is likely attributed, at least in part, to elevated superoxide generation and/or attenuated SOD activity in that population.

SOD has been proposed to be a transcriptional target of the VDR (Fig. 2), such that SOD expression is increased with vitamin D supplementation or direct cellular treatment with 1,25(OH)₂D₃ (8, 91). Additionally, vitamin D may suppress nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase)-induced production of superoxide radicals (24, 45). Together, these data provide potential mechanisms through which vitamin D bioavailability may modulate oxidative stress-induced vascular dysfunction, although this has yet to be explored. Moreover, vitamin D signals for the transcription of eNOS (4) and thus may improve NO bioavailability independently of reductions in oxidative stress. Because UV-B exposure in regions of relatively low sun exposure or high seasonal variation may not offer adequate UV-B-induced vitamin D biosynthesis in darkly pigmented populations, either UV-B therapy or vitamin D supplementation may be efficacious for upregulating eNOS and SOD expression and/or inhibiting superoxide production by NADPH oxidase, thereby improving vascular function.

Clinical recommendations for the evaluation, treatment, and prevention of vitamin D deficiency suggest screening in individuals at risk of deficiency (31, 68), including older adults (age ≥60 yr), those with obesity and/or malabsorption syndromes, or those with darker skin pigmentation. Daily vitamin D supplementation of 800 IU/day is recommended for darkly pigmented and older populations, although larger doses may be necessary for deficient individuals to attain sufficient serum 25(OH)D concentrations of at least 30 ng/mL for the maintenance of musculoskeletal and cardiovascular health (68). Table 1 presents a synopsis of studies examining the impact of vitamin D supplementation on vascular outcomes. Those studies have been limited mostly to overweight adults or patient populations such as those with type 2 diabetes mellitus or chronic kidney disease (26, 88, 90). In an asymptomatic vitamin D-deficient cohort, however, endothelial function (assessed via FMD) was blunted compared with a vitamin D-sufficient control group (75). In the deficient subjects, 3 mo of vitamin D treatment improved FMD such that it no longer differed from the control group. However, that study made no mention of skin pigmentation or genetic characteristics of its participants. To our knowledge, there has yet to be any investigation into the potential influence of either vitamin D supplementation or UV-B exposure treatment on endothelial function in an otherwise healthy African-American population. Therefore, future investigation is needed to elucidate the role of vitamin D in vascular endothelial function in this population and others with darkened skin pigmentation but varying in genetics and sociocultural environments.

**Table 1. Studies examining effects of vitamin D supplementation on endothelial function**
Reference	Participants	No. of Cases	Vitamin D Treatment	Outcome Measure	Results
Sugden et al. (2008)	Type 2 diabetes mellitus patients	17 Vitamin D treated 17 placebo	100,000 IU Vitamin D₂ or placebo	Brachial artery FMD	↑ [25-OH-D] by 15.3 nmol/L Improved FMD by 2.3% ↓ SBP 7.5 mmHg
Tarcin et al. (2009)	Healthy young vitamin D-deficient subjects	23 Vitamin D treated 23 normal controls	300,000 IU Vitamin D₃ monthly for 3 mo	Brachial artery FMD	↑ in [25-OH-D] of 96.5 nmol/L Improved FMD by 3.4%
Harris et al. (2011)	Overweight African-American adults	22 Vitamin D treated 23 placebo	60,000 IU Monthly oral vitamin D₃ or placebo for 16 wk	Brachial artery FMD	↑ [25-OH-D] by 66.6 nmol/L Improved FMD by 1.8% ↑ absolute diameter by 0.005 cm Improved FMD/shear by 0.08%·s⁻¹
Forman et al. (2013)	Black men and women in the United States	283 Vitamin D treated	1,000 IU (n = 68), 2,000 IU (n = 73), or 4,000 IU (n = 70) Vitamin D₃, or placebo (n = 72)	Blood pressure	Dose-dependent ↑ in [25-OH-D] of 13.4, 20.3, and 30.3 ng/mL Dose-dependent ↓ in MAP of 1.93, 2.0, and 2.46 mmHg versus ↑ MAP of 1.49 mmHg in placebo
Witham et al. (2013)	Patients with history of myocardial infarction	39 Vitamin D treated 36 placebo	300,000 IU Vitamin D₃ or placebo over 4 mo	Reactive hyperemia index	↑ in [25-OH-D] of 13 nmol/L after 6 mo No change in reactive hyperemia index
Yiu et al. (2013)	Type 2 diabetes mellitus patients	50 Vitamin D treated 50 placebo	5,000 IU daily Vitamin D₃ or placebo for 12 wk	Brachial artery FMD, brachial-ankle PWV	↑ in [25-OH-D] of 37.5 ng/mL No changes in FMD or PWV
Kumar et al. (2017)	Stage 3–4 CKD patients with vitamin D deficiency	58 Vitamin D treated 59 placebo	300,000 IU Vitamin D₃ or placebo at baseline and after 8 wk	Brachial artery FMD and NMD	↑ in [25-OH-D] of 24.9 ng/mL Improved FMD by 5.4% Improved NMD by 2.1%
Zhang et al. (2018)	Non-dialysis CKD patients	71 Vitamin D treated	50,000 IU Vitamin D₃ weekly for 12 wk	Brachial artery FMD	↑ in [25-OH-D] of 20.5 ng/mL Improved FMD by 0.7%

UVR, FOLATE METABOLISM, AND VASCULAR FUNCTION

Humans lack the ability to endogenously produce folate (vitamin B9), and rely on dietary sources or supplementation with folic acid (the synthetic form of folate) to meet biological requirements. The role of folate/folic acid in vascular function and health (Fig. 3) has been previously reviewed in depth (71) and is therefore beyond the scope of the present review. Briefly, ingested folate or folic acid is converted into the bioactive folate metabolite 5-MTHF. 5-MTHF may improve NO bioavailability and, thus, vascular function by promoting stabilization of the eNOS dimer via increased production of the eNOS cofactor tetrahydrobiopterin (BH₄) from its inactive form dihydrobiopterin (BH₂). Additionally, 5-MTHF may act as an antioxidant, directly scavenging ROS, which may otherwise reduce NO bioavailability by destabilizing eNOS or directly interacting with NO to produce peroxynitrite (ONOO⁻). Thus, high-dose folic acid supplementation may improve endothelial function in populations with overt cardiovascular and metabolic disease and endothelial dysfunction or even protect endothelial function in healthy adults (71).

**Fig. 3.**5-Methyltetrahydrofolate (5-MTHF) may augment vascular function through increased nitric oxide (NO) production and bioavailability. Ultraviolet-B (UV-B) may reduce 5-MTHF bioavailability via direct photodegradation. Ultraviolet-A (UV-A) and/or UV-B may indirectly reduce 5-MTHF bioavailability by increasing production of reactive oxygen species (ROS) which, in turn, scavenge available 5-MTHF. Increased melanin in the skin may reduce UV-A- and/or UV-B-induced photodegradation of 5-MTHF. BH₂, dihydrobiopterin; BH₄, tetrahydrobiopterin; NOS, nitric oxide synthase; $O_{2}^{-}$ , superoxide; ONOO⁻ , peroxinitrite. [Adapted from Stanhewicz and Kenney (71) with permission.]

Exposure of the skin to UVR may deplete bioavailable 5-MTHF. 5-MTHF is directly degraded by UV-B, but not by UV-A, in vitro (53, 72), although it is unclear whether UV-B directly degrades 5-MTHF in vivo due to its limited ability to penetrate the dermis. Alternatively, UV-A and/or UV-B radiation may indirectly degrade 5-MTHF via UVR-induced increases in oxidative stress (72, 73). However, studies examining the impact of UVR exposure on bioavailable folate in vivo are equivocal. Table 2 provides a summary of in vivo studies examining the impact of UVR exposure on folate status. Based on the available evidence, it appears that folate degradation in response to UVR exposure is likely dose dependent, requiring relatively large doses and/or prolonged, repeated exposures to observe reductions in serum and/or red blood cell folate.

**Table 2. Studies examining effects of UVR exposure on folate bioavailability**
Reference	Participants	No. of Cases	UVR Treatment	Outcome Measure	Results
Branda and Eaton (1978)	Light skinned dermatologic patients and healthy controls	10 UVR exposed patients 64 non-exposed healthy controls	4.5–9.5 J/cm² UV-A, 30–60 min once or twice weekly, minimum of 3 mo	SF concentration	Significantly lower SF concentrations in patients compared with controls
Gambichler et al. (2001)	Healthy adults; skin type II	8 UVR exposed 16 control	16 J/cm² UV-A, 2x weekly for 3 wk	SF concentration	No effect on serum folate
Shaheen et al. (2006)	Vitiligo patients and healthy controls; skin types I–III	20 Vitiligo patients 20 unexposed healthy controls	Cumulative 76 J/cm² nUV-B over 36 sessions	SF concentration	Significantly reduced serum folate in nUV-B treated patients
Rose et al. (2009)	Psoriasis patients with skin types I–III	35	Average of 2.3 J/cm² nUV-B per session; minimum of 18 sessions over 6 wk	SF and RCF concentrations	No effect of nUV-B exposure on either SF or RCF concentrations
Borradale et al. (2014)	Healthy women	45	Personal UVR exposure, measured with UV radiometer	SF concentration	Significant, negative relation between sun exposure and SF
Lucock et al. (2016)	Adults 65–95 yr of age	639	Accumulated exposure over 42 and 120 days	RCF concentration	Significant, negative relation between accumulated exposure and RCF
Valencia-Vera et al. (2019)	Primary and secondary health care patients	Study 1: 118,831 samples Study 2: 1,597 patients with repeated measures	Daily environmental UVR exposure	SF concentration	Decreased folate status in summer compared with winter; greater prevalence of deficiency in summer

Potential Determinants of UVR-Induced 5-MTHF Metabolism

Skin pigmentation.

A darkened constitutive skin pigmentation appears to play a protective role against photodegradation of 5-MTHF by UVR (35, 47), attributable to absorption of UVR by melanocytes in the skin. Because UV-A penetrates more deeply into the skin, its transmission through the skin is more dependent on melanin concentration than is UV-B (3, 28). Thus, the ability of UV-A (compared with UV-B) to influence bioavailable 5-MTHF in the cutaneous circulation may be more limited in those with darker skin pigments. This is particularly important in light of the fact that UV-A accounts for ~95% of the UVR that reaches the earth's surface from the sun (5). Additionally, immediate pigment darkening after an initial UVR exposure protects against photosensitization of 5-MTHF by riboflavin and uroporphyrin during subsequent exposures (53), and development of immediate pigment darkening is greater in those with darker compared with lighter constitutive pigments (61).

Genetics.

In addition to the influence of skin pigmentation, variation in the 5-MTHF response to UVR exposure may also be explained, at least in part, by genetic variation (51). Of particular interest is the MTHFR gene, responsible for encoding the transcription of the enzyme methylenetetrahydrofolate reductase (MTHFR), which converts 5,10 methylenetetrahydrofolate to 5-MTHF. Lucock et al. (51) examined the association between UVR exposure and folate status in carriers of the C677T-MTHFR gene polymorphism. They demonstrated a significant negative relation between red cell folate concentrations and accumulated UVR exposure over 42 days for those who carry the T allele (677CT and 677TT genotypes), but not for those with the 677CC genotype. Furthermore, the relation was stronger for carriers of the 677TT compared with the 677CT genotype, suggesting a progressive increase in UVR-induced folate depletion with increasing presence of the polymorphic T allele. Subsequently, the same group observed associations between skin pigmentation and genes related to folate metabolism, including the MTHFR gene, suggesting that various folate genotypes may be selected for in different UVR environments (38). It may be that expression of folate-related genes is suppressed for those with darker skin pigments and/or those carrying a genotype that preserves activity of folate metabolism who are living in relatively low UVR environments. Expression of those genes, however, may be upregulated when folate status is reduced. Indeed, DNA methylation was upregulated when plasma or red blood cell folate concentrations fell below 12 nmol/L in individuals with the 677CC, but not the 677TT, genotype (23), suggesting that variants of the MTHFR gene elicit differential epigenetic responses to reduced folate status.

UVR Effects on 5-MTHF and Vascular Function

Recent research from our laboratory has demonstrated that exposure of skin of the ventral forearm to 300 mJ/cm² UV-B (85) or 450 mJ/cm² broad-spectrum UVR (combined UV-A and UV-B) (84) attenuates NO-mediated vasodilation of the cutaneous microvasculature compared with nonexposed skin on the contralateral forearm in healthy, young adults. In the former of those two studies, we demonstrated that direct perfusion of either 5-MTHF or ascorbate (a nonspecific antioxidant) to local areas of the UV-B-exposed skin restored postexposure microvascular function, such that there were no differences in NO-mediated vasodilation between those two sites or compared with the nonexposed control site (Fig. 4). Data from that study suggest that reductions in NO-mediated vasodilation after UV-B exposure were due to photodegradation of 5-MTHF directly by UV-B exposure and/or indirectly via UV-B-induced increases in ROS. In the latter study (84), we further demonstrated that application of sunscreen to the skin before broad-spectrum UVR exposure protected NO-mediated vasodilation. Of note, although the NO contribution to the dilator response during local heating was attenuated after UVR exposure in those studies, the overall magnitude of the dilatory response was unaltered, suggesting upregulation of compensatory dilatory pathways (e.g., endothelium-derived hyperpolarizing factors) in the face of reduced NO bioavailability. However, reductions in NO bioavailability and NO-mediated microvascular function are associated with increased long-term risk of CVD (39, 55); thus, reductions in NO-mediated vasodilation after UVR exposure may suggest risk of future endothelial dysfunction with chronic overexposure to UVR.

**Fig. 4.**Percent nitric oxide (%NO) contribution to the vasodilatory response to local heating in nonexposed skin (open bar), ultraviolet-B (UV-B)-exposed skin (filled bar), and UV-B-exposed skin with local perfusion of ascorbate (ASC; hashed bar) or 5-methyltetrahydrofolate (5-MTHF; shaded bar). *P < 0.05 vs. nonexposed skin; †P < 0.05 vs. UV-B-exposed skin.

We also examined whether differences in skin pigmentation would influence the magnitude of the reduction in NO-mediated vasodilation after UV-B exposure (85). Twenty-two subjects were recruited with a wide range of melanin indexes (M-index; a measure of skin pigmentation, as measured by skin spectrophotometry), and there was no relation between M-index and the magnitude of the reduction in NO-dependent dilation after acute UV-B exposure. It may be that those with light and dark skin pigmentation are similarly susceptible to the acute (i.e., single exposure) effects of UVR exposure on NO-mediated vasodilation, but those with a darker pigment are better able to adapt and protect against repeated exposures due to immediate pigment darkening and/or increased folate metabolism in response to UVR exposure. Future investigation is warranted to elucidate the role of skin pigmentation and folate metabolism-related genes in the vascular response to UVR.

Although we (84, 85) demonstrated acute reductions in NO-mediated vasodilation in the cutaneous microvasculature after local UVR exposure, it remains unclear whether whole body UVR exposure may influence systemic vascular function. Oral administration of folic acid has been demonstrated to improve FMD (19, 49, 76) in patients with coronary artery disease or hypercholesterolemia. However, there has yet to be investigation into whether reductions in bioavailable folate after UVR exposure may impair conduit artery and systemic vascular function. Similarly, our laboratory previously demonstrated that either direct perfusion of 5-MTHF or oral folic acid supplementation improved microvascular responses to local heating in older adults (≥65 yr) with impaired microvascular function compared with young adults (18–30 yr), such that microvascular responses were no longer different between groups (70). In that study, older and young adults had similar baseline plasma 5-MTHF concentrations, suggesting that elevated 5-MTHF bioavailability promotes healthy vascular function in an older population. Although the effects of UVR on vascular function have yet to be investigated in older adults, those data suggest that UVR-induced 5-MTHF degradation may exacerbate the vascular effects of UVR in that population.

NONFOLATE, NONVITAMIN D EFFECTS OF UVR ON SKIN VASCULAR FUNCTION

UVR exposure may exert effects on vascular health and function independently of those mediated by folate or vitamin D metabolism. Exposure of human skin keratinocytes to UV-A or UV-B radiation elicits significant increases in ROS (78, 79). Furthermore, cells pretreated with apocynin (79) or diphenylene iodonium (78, 79) suppressed ROS formation such that it did not change from baseline, suggesting that NADPH oxidase is likely a primary source of UV-B-induced ROS production (79). NADPH oxidase generates ROS by catalyzing the removal of an electron from NADPH, of which the final acceptor is molecular oxygen, resulting in the production of superoxide radicals (20). Increased production of superoxide may further promote ROS production by reacting with NO to produce peroxynitrite (10). ROS produced via this cascade of events, particularly ONOO⁻ (46), may oxidize the eNOS cofactor BH₄, resulting in uncoupling of the eNOS dimer (44) and subsequent production of superoxide by uncoupled eNOS (27). Thus, UVR may elicit deleterious vascular effects independently of 5-MTHF degradation. However, the impact of such UVR-induced ROS production on vascular function after acute and/or chronic exposures and the role of skin pigmentation in modulating these responses remain unclear. Additionally, the interplay between UVR-induced NADPH oxidase activity and vitamin D-induced suppression of NADPH oxidase is unclear.

In addition to its role in ROS production, UVR may also elicit inflammatory responses that influence vascular function and health. In an ex vivo model, exposure of human dermal microvascular endothelial cells to 2–4 minimal erythema doses of UV-B resulted in upregulation of mRNA expression and production of IL-1β, IL-6, IL-8, and chemokine (C-X-C motif) ligand 1 (CXCL1; also called growth-regulated oncogene-α, GROα) cytokines (64). We and others (22, 82) have demonstrated dose- and time-dependent increases in resting skin blood flow in vivo after UV-B or broad-spectrum UVR exposure, beginning in the first 6 h postexposure (84) and continuing to develop over 24 h. UV-B-induced skin blood flow responses were blunted by infusion of indomethacin and/or N ^G-monomethyl-l-arginine (l-NMMA), suggesting that the increases in skin blood flow were mediated by inflammation-induced upregulation of cyclooxygenase and/or inducible NOS (iNOS) (82). Our recent study demonstrated that the erythema and blood flow responses to an erythemogenic dose of broad-spectrum UVR in light to moderately pigmentated (M-index, 30–49; Fitzpatrick skin type, I-IV) subjects were temporally distinct, suggesting that skin blood flow responses were not simply a function of skin reddening (84). Importantly, vascular inflammation and overexpression of inflammatory cytokines are associated with vascular dysfunction, atherosclerosis, and vascular disease (69). Therefore, chronic overexposure to UVR could potentially play a role in inflammation-related vascular dysfunction and aging. Although our study did not include darkly pigmented subjects, darkly pigmented skin requires substantially larger doses of UVR to elicit an erythema response (32), and it is therefore likely that a darkened pigment would be similarly protective against the vascular inflammatory effects of UVR. Future research is warranted to examine the influence of skin pigmentation on vascular inflammation after UVR exposure.

Exposure of human skin to UV-A radiation has also been proposed to acutely increase NO production (50, 54, 58), but it may (50, 58) or may not (54) reduce blood pressure. The NO-producing effect of UV-A appears to be mediated by liberation of NO via photolysis of cutaneous nitrite stores (58) and is independent of NOS (50). Furthermore, because these effects were elicited by exposure of the skin to UV-A and not UV-B, these results suggest a potential role for UVR in vascular health separate from vitamin D. However, in those studies showing reductions in blood pressure, blood pressure and NO concentrations returned to baseline 20–60 min after UV-A exposure, and it is therefore unclear whether this effect provides any long-term health benefits. Because of absorbance of UV-A by melanocytes in the skin, it is likely that increasingly larger doses of UV-A would be required to observe these effects with increasing skin pigmentation, although this has yet to be explored.

Perspectives and Significance

Exposure to UVR from the sun is associated with both beneficial and deleterious effects on cutaneous vascular health. Both folate and vitamin D play important roles in healthy vascular function, but UVR exposure elicits opposing effects on metabolism and bioavailability of these two compounds. The effects of UVR on folate and vitamin D metabolism appear to be influenced by multiple factors, including skin pigmentation, genetics, geographical location, and age. Beyond the influence of UVR on folate and vitamin D metabolism, UVR exposure may cause oxidative stress and inflammatory responses that impair vascular health in a dose-dependent fashion. As such, under- or overexposure to UVR may be differentially related to vascular dysfunction and elevated risk of cardiovascular disease in diverse populations. Currently available data are limited to studies examining the acute impact of UVR on vascular health, and it is therefore unclear how long-term, chronic exposure to UVR influences vascular function in various populations. The literature reviewed herein demonstrates the complexity of the interactions between individual characteristics and environment in modulating vitamin D and folate bioavailability and vascular health. The existing data suggest that adequate UVR exposure to maintain normal vitamin D concentrations may be important for cardiovascular health but that overexposure may result in reduced folate status and deleterious vascular effects. It is currently unclear, however, how the ideal amount of UVR exposure varies based on individual characteristics. Further clinical trials are needed to better understand the optimal balance of sun exposure to protect cardiovascular health and how this balance may differ between and within populations.

GRANTS

S. T. Wolf is supported by a grant from the National Institutes of Health (NIH T-32 Grant 5T32AG049676-03).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

S.T.W. and W.L.K. conceived and designed research; S.T.W. prepared figures; S.T.W. drafted manuscript; S.T.W. and W.L.K. edited and revised manuscript; S.T.W. and W.L.K. approved final version of manuscript.

REFERENCES

1. Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, Li Q, Weinstein SJ, Purdue M, Virtamo J, Horst R, Wheeler W, Chanock S, Hunter DJ, Hayes RB, Kraft P, Albanes D. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19: 2739–2745, 2010. doi:10.1093/hmg/ddq155.
Crossref | PubMed | ISI | Google Scholar
2. Al Mheid I, Patel R, Murrow J, Morris A, Rahman A, Fike L, Kavtaradze N, Uphoff I, Hooper C, Tangpricha V, Alexander RW, Brigham K, Quyyumi AA. Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans. J Am Coll Cardiol 58: 186–192, 2011. doi:10.1016/j.jacc.2011.02.051.
Crossref | PubMed | ISI | Google Scholar
3. Anderson RR, Parrish JA. The optics of human skin. J Invest Dermatol 77: 13–19, 1981. doi:10.1111/1523-1747.ep12479191.
Crossref | PubMed | ISI | Google Scholar
4. Andrukhova O, Slavic S, Zeitz U, Riesen SC, Heppelmann MS, Ambrisko TD, Markovic M, Kuebler WM, Erben RG. Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice. Mol Endocrinol 28: 53–64, 2014. doi:10.1210/me.2013-1252.
Crossref | PubMed | Google Scholar
5. Baron ED, Suggs AK. Introduction to photobiology. Dermatol Clin 32: 255–266, 2014. doi:10.1016/j.det.2014.03.002.
Crossref | PubMed | ISI | Google Scholar
6. Beak SM, Lee YS, Kim JA. NADPH oxidase and cyclooxygenase mediate the ultraviolet B-induced generation of reactive oxygen species and activation of nuclear factor-kappaB in HaCaT human keratinocytes. Biochimie 86: 425–429, 2004. doi:10.1016/j.biochi.2004.06.010.
Crossref | PubMed | ISI | Google Scholar
7. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation 135: e146–e603, 2017. [Erratum in Circulation 136: e196, 2017.] doi:10.1161/CIR.0000000000000485.
Crossref | PubMed | ISI | Google Scholar
8. Bhat M, Ismail A. Vitamin D treatment protects against and reverses oxidative stress induced muscle proteolysis. J Steroid Biochem Mol Biol 152: 171–179, 2015. doi:10.1016/j.jsbmb.2015.05.012.
Crossref | PubMed | ISI | Google Scholar
9. Bikle D. Vitamin D: production, metabolism, and mechanisms of action. In: Endotext , edited by De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A. South Dartmouth, MA: MDText.com, https://www.ncbi.nlm.nih.gov/books/NBK278943. 2000.
Google Scholar
10. Blough NV, Zafiriou OC. Reaction of superoxide with nitric oxide to form peroxonitrite in alkaline aqueous solution. Inorg Chem 24: 3502–3504, 1985. doi:10.1021/ic00216a003.
Crossref | ISI | Google Scholar
11. Campia U, Choucair WK, Bryant MB, Waclawiw MA, Cardillo C, Panza JA. Reduced endothelium-dependent and -independent dilation of conductance arteries in African Americans. J Am Coll Cardiol 40: 754–760, 2002. doi:10.1016/S0735-1097(02)02015-6.
Crossref | PubMed | ISI | Google Scholar
12. Cannon RO III. Role of nitric oxide in cardiovascular disease: focus on the endothelium. Clin Chem 44: 1809–1819, 1998.
PubMed | ISI | Google Scholar
13. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 101: 7711–7715, 2004. doi:10.1073/pnas.0402490101.
Crossref | PubMed | ISI | Google Scholar
14. Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 319: 74–76, 1982. doi:10.1016/S0140-6736(82)90214-8.
Crossref | PubMed | Google Scholar
15. Datta P, Philipsen PA, Olsen P, Petersen B, Andersen JD, Morling N, Wulf HC. Pigment genes not skin pigmentation affect UVB-induced vitamin D. Photochem Photobiol Sci 18: 448–458, 2019. doi:10.1039/C8PP00320C.
Crossref | PubMed | ISI | Google Scholar
16. Davie M, Lawson DE. Assessment of plasma 25-hydroxyvitamin D response to ultraviolet irradiation over a controlled area in young and elderly subjects. Clin Sci (Lond) 58: 235–242, 1980. doi:10.1042/cs0580235.
Crossref | PubMed | ISI | Google Scholar
17. Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, Josse RG, Lips P, Morales-Torres J, Yoshimura N. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int 21: 1151–1154, 2010. doi:10.1007/s00198-010-1285-3.
Crossref | PubMed | ISI | Google Scholar
18. Diffey BL. Sources and measurement of ultraviolet radiation. Methods 28: 4–13, 2002. doi:10.1016/S1046-2023(02)00204-9.
Crossref | PubMed | ISI | Google Scholar
19. Doshi SN, McDowell IF, Moat SJ, Lang D, Newcombe RG, Kredan MB, Lewis MJ, Goodfellow J. Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide? Arterioscler Thromb Vasc Biol 21: 1196–1202, 2001. doi:10.1161/hq0701.092000.
Crossref | PubMed | ISI | Google Scholar
20. Drummond GR, Selemidis S, Griendling KK, Sobey CG. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 10: 453–471, 2011. doi:10.1038/nrd3403.
Crossref | PubMed | ISI | Google Scholar
21. Dupont E, Gomez J, Bilodeau D. Beyond UV radiation: a skin under challenge. Int J Cosmet Sci 35: 224–232, 2013. doi:10.1111/ics.12036.
Crossref | PubMed | ISI | Google Scholar
22. Farr PM, Diffey BL. The vascular response of human skin to ultraviolet radiation. Photochem Photobiol 44: 501–507, 1986. doi:10.1111/j.1751-1097.1986.tb04699.x.
Crossref | PubMed | ISI | Google Scholar
23. Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 99: 5606–5611, 2002. doi:10.1073/pnas.062066299.
Crossref | PubMed | ISI | Google Scholar
24. Nakai K, Fujii H, Kono K, Goto S, Kitazawa R, Kitazawa S, Hirata M, Shinohara M, Fukagawa M, Nishi S. Vitamin D activates the Nrf2-Keap1 antioxidant pathway and ameliorates nephropathy in diabetic rats. Am J Hypertens 27: 586–595, 2014. doi:10.1093/ajh/hpt160.
Crossref | PubMed | ISI | Google Scholar
25. Gokce N, Holbrook M, Duffy SJ, Demissie S, Cupples LA, Biegelsen E, Keaney JF Jr, Loscalzo J, Vita JA. Effects of race and hypertension on flow-mediated and nitroglycerin-mediated dilation of the brachial artery. Hypertension 38: 1349–1354, 2001. doi:10.1161/hy1201.096575.
Crossref | PubMed | ISI | Google Scholar
26. Harris RA, Pedersen-White J, Guo DH, Stallmann-Jorgensen IS, Keeton D, Huang Y, Shah Y, Zhu H, Dong Y. Vitamin D3 supplementation for 16 weeks improves flow-mediated dilation in overweight African-American adults. Am J Hypertens 24: 557–562, 2011. doi:10.1038/ajh.2011.12.
Crossref | PubMed | ISI | Google Scholar
27. Harrison DG, Chen W, Dikalov S, Li L. Regulation of endothelial cell tetrahydrobiopterin pathophysiological and therapeutic implications. Adv Pharmacol 60: 107–132, 2010. doi:10.1016/B978-0-12-385061-4.00005-2.
Crossref | PubMed | Google Scholar
28. Hoffmann K, Kaspar K, Altmeyer P, Gambichler T. UV transmission measurements of small skin specimens with special quartz cuvettes. Dermatology 201: 307–311, 2000. doi:10.1159/000051543.
Crossref | PubMed | ISI | Google Scholar
29. Holick MF. Vitamin D deficiency. N Engl J Med 357: 266–281, 2007. doi:10.1056/NEJMra070553.
Crossref | PubMed | ISI | Google Scholar
30. Holick MF. Vitamin D: A millenium perspective. J Cell Biochem 88: 296–307, 2003. doi:10.1002/jcb.10338.
Crossref | PubMed | ISI | Google Scholar
31. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96: 1911–1930, 2011. doi:10.1210/jc.2011-0385.
Crossref | PubMed | ISI | Google Scholar
32. Hönigsmann H. Erythema and pigmentation. Photodermatol Photoimmunol Photomed 18: 75–81, 2002. doi:10.1034/j.1600-0781.2002.180204.x.
Crossref | PubMed | ISI | Google Scholar
33. Hurr C, Patik JC, Kim K, Christmas KM, Brothers RM. Tempol augments the blunted cutaneous microvascular thermal reactivity in healthy young African Americans. Exp Physiol 103: 343–349, 2018. doi:10.1113/EP086776.
Crossref | PubMed | ISI | Google Scholar
34. Jablonski KL, Chonchol M, Pierce GL, Walker AE, Seals DR. 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults. Hypertension 57: 63–69, 2011. doi:10.1161/HYPERTENSIONAHA.110.160929.
Crossref | PubMed | ISI | Google Scholar
35. Jablonski NG, Chaplin G. Human skin pigmentation as an adaptation to UV radiation. Proc Natl Acad Sci USA 107, Suppl 2: 8962–8968, 2010. doi:10.1073/pnas.0914628107.
Crossref | PubMed | ISI | Google Scholar
36. Jablonski NG, Chaplin G. The evolution of human skin coloration. J Hum Evol 39: 57–106, 2000. doi:10.1006/jhev.2000.0403.
Crossref | PubMed | ISI | Google Scholar
37. Jablonski NG, Chaplin G. The roles of vitamin D and cutaneous vitamin D production in human evolution and health. Int J Paleopathol 23: 54–59, 2018. doi:10.1016/j.ijpp.2018.01.005.
Crossref | PubMed | ISI | Google Scholar
38. Jones P, Lucock M, Veysey M, Jablonski N, Chaplin G, Beckett E. Frequency of folate-related polymorphisms varies by skin pigmentation. Am J Hum Biol 30: e23079, 2018. doi:10.1002/ajhb.23079.
Crossref | PubMed | ISI | Google Scholar
39. Kenney WL. Edward F. Adolph Distinguished Lecture: Skin-deep insights into vascular aging. J Appl Physiol (1985) 123: 1024–1038, 2017. doi:10.1152/japplphysiol.00589.2017.
Link | ISI | Google Scholar
40. Kim DH, Sabour S, Sagar UN, Adams S, Whellan DJ. Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004). Am J Cardiol 102: 1540–1544, 2008. doi:10.1016/j.amjcard.2008.06.067.
Crossref | PubMed | ISI | Google Scholar
41. Kim K, Hurr C, Patik JC, Matthew Brothers R. Attenuated cutaneous microvascular function in healthy young African Americans: Role of intradermal l-arginine supplementation. Microvasc Res 118: 1–6, 2018. doi:10.1016/j.mvr.2018.02.001.
Crossref | PubMed | ISI | Google Scholar
42. Krause R, Bühring M, Hopfenmüller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet 352: 709–710, 1998. doi:10.1016/S0140-6736(05)60827-6.
Crossref | PubMed | ISI | Google Scholar
43. Kuan V, Martineau AR, Griffiths CJ, Hyppönen E, Walton R. DHCR7 mutations linked to higher vitamin D status allowed early human migration to northern latitudes. BMC Evol Biol 13: 144, 2013. doi:10.1186/1471-2148-13-144.
Crossref | PubMed | ISI | Google Scholar
44. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111: 1201–1209, 2003. doi:10.1172/JCI200314172.
Crossref | PubMed | ISI | Google Scholar
45. Dong J, Wong SL, Lau CW, Lee HK, Ng CF, Zhang L, Yao X, Chen ZY, Vanhoutte PM, Huang Y. Calcitriol protects renovascular function in hypertension by down-regulating angiotensin II type 1 receptors and reducing oxidative stress. Eur Heart J 33: 2980–2990, 2012. doi:10.1093/eurheartj/ehr459.
Crossref | PubMed | ISI | Google Scholar
46. Laursen JB, Somers M, Kurz S, McCann L, Warnholtz A, Freeman BA, Tarpey M, Fukai T, Harrison DG. Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 103: 1282–1288, 2001. doi:10.1161/01.CIR.103.9.1282.
Crossref | PubMed | ISI | Google Scholar
47. Lawrence VA. Demographic analysis of serum folate and folate-binding capacity in hospitalized patients. Acta Haematol 69: 289–293, 1983. doi:10.1159/000206909.
Crossref | PubMed | ISI | Google Scholar
48. Lehmann B, Sauter W, Knuschke P, Dressler S, Meurer M. Demonstration of UVB-induced synthesis of 1 alpha,25-dihydroxyvitamin D3 (calcitriol) in human skin by microdialysis. Arch Dermatol Res 295: 24–28, 2003. doi:10.1007/s00403-003-0387-6.
Crossref | PubMed | ISI | Google Scholar
49. Lekakis JP, Papamichael CM, Papaioannou TG, Dagre AG, Stamatelopoulos KS, Tryfonopoulos D, Protogerou AD, Stamatelopoulos SF, Mavrikakis M. Oral folic acid enhances endothelial function in patients with hypercholesterolaemia receiving statins. Eur Cardiovasc J Prev Rehab 11: 416–420, 2004. doi:10.1097/01.hjr.0000206331.10791.ad.
Crossref | PubMed | Google Scholar
50. Liu D, Fernandez BO, Hamilton A, Lang NN, Gallagher JMC, Newby DE, Feelisch M, Weller RB. UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase. J Invest Dermatol 134: 1839–1846, 2014. doi:10.1038/jid.2014.27.
Crossref | PubMed | ISI | Google Scholar
51. Lucock M, Beckett E, Martin C, Jones P, Furst J, Yates Z, Jablonski NG, Chaplin G, Veysey M. UV-associated decline in systemic folate: implications for human nutrigenetics, health, and evolutionary processes. Am J Hum Biol 29: e22929, 2017. doi:10.1002/ajhb.22929.
Crossref | PubMed | ISI | Google Scholar
52. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 76: 1536–1538, 1985. doi:10.1172/JCI112134.
Crossref | PubMed | ISI | Google Scholar
53. Moan J, Nielsen KP, Juzeniene A. Immediate pigment darkening: its evolutionary roles may include protection against folate photosensitization. FASEB J 26: 971–975, 2012. doi:10.1096/fj.11-195859.
Crossref | PubMed | ISI | Google Scholar
54. Monaghan C, McIlvenna LC, Liddle L, Burleigh M, Weller RB, Fernandez BO, Feelisch M, Muggeridge DJ, Easton C. The effects of two different doses of ultraviolet-A light exposure on nitric oxide metabolites and cardiorespiratory outcomes. Eur J Appl Physiol 118: 1043–1052, 2018. doi:10.1007/s00421-018-3835-x.
Crossref | PubMed | ISI | Google Scholar
55. Naseem KM. The role of nitric oxide in cardiovascular diseases. Mol Aspects Med 26: 33–65, 2005. doi:10.1016/j.mam.2004.09.003.
Crossref | PubMed | Google Scholar
56. Nesby-O'Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, Allen C, Doughertly C, Gunter EW, Bowman BA. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 76: 187–192, 2002. doi:10.1093/ajcn/76.1.187.
Crossref | PubMed | ISI | Google Scholar
57. Noon JP, Walker BR, Webb DJ, Shore AC, Holton DW, Edwards HV, Watt GC. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 99: 1873–1879, 1997. doi:10.1172/JCI119354.
Crossref | PubMed | ISI | Google Scholar
58. Opländer C, Volkmar CM, Paunel-Görgülü A, van Faassen EE, Heiss C, Kelm M, Halmer D, Mürtz M, Pallua N, Suschek CV. Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates. Circ Res 105: 1031–1040, 2009. doi:10.1161/CIRCRESAHA.109.207019.
Crossref | PubMed | ISI | Google Scholar
59. Pilz S, Tomaschitz A, Ritz E, Pieber TR. Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol 6: 621–630, 2009. doi:10.1038/nrcardio.2009.135.
Crossref | PubMed | ISI | Google Scholar
60. Reddy Vanga S, Good M, Howard PA, Vacek JL. Role of vitamin D in cardiovascular health. Am J Cardiol 106: 798–805, 2010. doi:10.1016/j.amjcard.2010.04.042.
Crossref | PubMed | ISI | Google Scholar
61. Routaboul C, Denis A, Vinche A. Immediate pigment darkening: description, kinetic and biological function. Eur J Dermatol 9: 95–99, 1999.
PubMed | ISI | Google Scholar
62. Scharffetter-Kochanek K, Wlaschek M, Brenneisen P, Schauen M, Blaudschun R, Wenk J. UV-induced reactive oxygen species in photocarcinogenesis and photoaging. Biol Chem 378: 1247–1257, 1997.
PubMed | ISI | Google Scholar
63. Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 71, Suppl: 1295S–1303S, 2000. doi:10.1093/ajcn/71.5.1295s.
Crossref | PubMed | ISI | Google Scholar
64. Scholzen T, Hartmeyer M, Fastrich M, Brzoska T, Becher E, Schwarz T, Luger TA. Ultraviolet light and interleukin-10 modulate expression of cytokines by transformed human dermal microvascular endothelial cells (HMEC-1). J Invest Dermatol 111: 50–56, 1998. doi:10.1046/j.1523-1747.1998.00229.x.
Crossref | PubMed | ISI | Google Scholar
65. Schuessler M, Astecker N, Herzig G, Vorisek G, Schuster I. Skin is an autonomous organ in synthesis, two-step activation and degradation of vitamin D(3): CYP27 in epidermis completes the set of essential vitamin D(3)-hydroxylases. Steroids 66: 399–408, 2001. doi:10.1016/S0039-128X(00)00229-4.
Crossref | PubMed | ISI | Google Scholar
66. Seals DR, Jablonski KL, Donato AJ. Aging and vascular endothelial function in humans. Clin Sci (Lond) 120: 357–375, 2011. doi:10.1042/CS20100476.
Crossref | PubMed | ISI | Google Scholar
67. Sklar LR, Almutawa F, Lim HW, Hamzavi I. Effects of ultraviolet radiation, visible light, and infrared radiation on erythema and pigmentation: a review. Photochem Photobiol Sci 12: 54–64, 2013. doi:10.1039/C2PP25152C.
Crossref | PubMed | ISI | Google Scholar
68. Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, Bischoff-Ferrari HA, Cavalier E, Ebeling PR, Fardellone P, Gandini S, Gruson D, Guérin AP, Heickendorff L, Hollis BW, Ish-Shalom S, Jean G, von Landenberg P, Largura A, Olsson T, Pierrot-Deseilligny C, Pilz S, Tincani A, Valcour A, Zittermann A. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev 9: 709–715, 2010. doi:10.1016/j.autrev.2010.06.009.
Crossref | PubMed | ISI | Google Scholar
69. Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78: 539–552, 2009. doi:10.1016/j.bcp.2009.04.029.
Crossref | PubMed | ISI | Google Scholar
70. Stanhewicz AE, Alexander LM, Kenney WL. Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms. Clin Sci (Lond) 129: 159–167, 2015. doi:10.1042/CS20140821.
Crossref | PubMed | ISI | Google Scholar
71. Stanhewicz AE, Kenney WL. Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutr Rev 75: 61–70, 2017. doi:10.1093/nutrit/nuw053.
Crossref | PubMed | ISI | Google Scholar
72. Steindal AH, Juzeniene A, Johnsson A, Moan J. Photodegradation of 5-methyltetrahydrofolate: biophysical aspects. Photochem Photobiol 82: 1651–1655, 2006. doi:10.1111/j.1751-1097.2006.tb09826.x.
Crossref | PubMed | ISI | Google Scholar
73. Tam TT, Juzeniene A, Steindal AH, Iani V, Moan J. Photodegradation of 5-methyltetrahydrofolate in the presence of Uroporphyrin. J Photochem Photobiol B 94: 201–204, 2009. doi:10.1016/j.jphotobiol.2008.12.003.
Crossref | PubMed | ISI | Google Scholar
74. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among free-living healthy young adults. Am J Med 112: 659–662, 2002. doi:10.1016/S0002-9343(02)01091-4.
Crossref | PubMed | ISI | Google Scholar
75. Tarcin O, Yavuz DG, Ozben B, Telli A, Ogunc AV, Yuksel M, Toprak A, Yazici D, Sancak S, Deyneli O, Akalin S. Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects. J Clin Endocrinol Metab 94: 4023–4030, 2009. doi:10.1210/jc.2008-1212.
Crossref | PubMed | ISI | Google Scholar
76. Title LM, Cummings PM, Giddens K, Genest JJ Jr, Nassar BA. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 36: 758–765, 2000. doi:10.1016/S0735-1097(00)00809-3.
Crossref | PubMed | ISI | Google Scholar
77. Tsai KS, Heath H III, Kumar R, Riggs BL. Impaired vitamin D metabolism with aging in women. Possible role in pathogenesis of senile osteoporosis. J Clin Invest 73: 1668–1672, 1984. doi:10.1172/JCI111373.
Crossref | PubMed | ISI | Google Scholar
78. Valencia A, Kochevar IE. Nox1-based NADPH oxidase is the major source of UVA-induced reactive oxygen species in human keratinocytes. J Invest Dermatol 128: 214–222, 2008. doi:10.1038/sj.jid.5700960.
Crossref | PubMed | ISI | Google Scholar
79. Wang H, Kochevar IE. Involvement of UVB-induced reactive oxygen species in TGF-beta biosynthesis and activation in keratinocytes. Free Radic Biol Med 38: 890–897, 2005. doi:10.1016/j.freeradbiomed.2004.12.005.
Crossref | PubMed | ISI | Google Scholar
80. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D'Agostino RB, Wolf M, Vasan RS. Vitamin D deficiency and risk of cardiovascular disease. Circulation 117: 503–511, 2008. doi:10.1161/CIRCULATIONAHA.107.706127.
Crossref | PubMed | ISI | Google Scholar
81. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O'Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Järvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hyppönen E, Spector TD. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376: 180–188, 2010. doi:10.1016/S0140-6736(10)60588-0.
Crossref | PubMed | ISI | Google Scholar
82. Warren JB. Nitric oxide and human skin blood flow responses to acetylcholine and ultraviolet light. FASEB J 8: 247–251, 1994. doi:10.1096/fasebj.8.2.7509761.
Crossref | PubMed | ISI | Google Scholar
84. Wolf ST, Berry CW, Stanhewicz AE, Kenney LE, Ferguson SB, Kenney WL. Sunscreen or simulated sweat minimizes the impact of acute ultraviolet radiation on cutaneous microvascular function in healthy humans. Exp Physiol 104: 1136–1146, 2019. doi:10.1113/EP087688.
Crossref | PubMed | Google Scholar
85. Wolf ST, Stanhewicz AE, Jablonski NG, Kenney WL. Acute ultraviolet radiation exposure attenuates nitric oxide-mediated vasodilation in the cutaneous microvasculature of healthy humans. J Appl Physiol (1985) 125: 1232–1237, 2018. doi:10.1152/japplphysiol.00501.2018.
Link | ISI | Google Scholar
86. Wölfle U, Esser PR, Simon-Haarhaus B, Martin SF, Lademann J, Schempp CM. UVB-induced DNA damage, generation of reactive oxygen species, and inflammation are effectively attenuated by the flavonoid luteolin in vitro and in vivo. Free Radic Biol Med 50: 1081–1093, 2011. doi:10.1016/j.freeradbiomed.2011.01.027.
Crossref | PubMed | ISI | Google Scholar
87. Yang HT, Lee M, Hong KS, Ovbiagele B, Saver JL. Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials. Eur J Intern Med 23: 745–754, 2012. doi:10.1016/j.ejim.2012.07.004.
Crossref | PubMed | ISI | Google Scholar
88. Yiu YF, Yiu KH, Siu CW, Chan YH, Li SW, Wong LY, Lee SW, Tam S, Wong EW, Lau CP, Cheung BM, Tse HF. Randomized controlled trial of vitamin D supplement on endothelial function in patients with type 2 diabetes. Atherosclerosis 227: 140–146, 2013. doi:10.1016/j.atherosclerosis.2012.12.013.
Crossref | PubMed | ISI | Google Scholar
89. Yousefzadeh P, Shapses SA, Wang X. Vitamin D binding protein impact on 25-hydroxyvitamin D levels under different physiologic and pathologic conditions. Int J Endocrinol 2014: 1, 2014. doi:10.1155/2014/981581.
Crossref | PubMed | Google Scholar
90. Zhang Q, Zhang M, Wang H, Sun C, Feng Y, Zhu W, Cao D, Shao Q, Li N, Xia Y, Tang T, Wan C, Liu J, Jin B, Zhao M, Jiang C. Vitamin D supplementation improves endothelial dysfunction in patients with non-dialysis chronic kidney disease. Int Urol Nephrol 50: 923–927, 2018. doi:10.1007/s11255-018-1829-6.
Crossref | PubMed | ISI | Google Scholar
91. Zhong W, Gu B, Gu Y, Groome LJ, Sun J, Wang Y. Activation of vitamin D receptor promotes VEGF and CuZn-SOD expression in endothelial cells. J Steroid Biochem Mol Biol 140: 56–62, 2014. doi:10.1016/j.jsbmb.2013.11.017.
Crossref | PubMed | ISI | Google Scholar

Folate And Vitamin D

Source: https://journals.physiology.org/doi/full/10.1152/ajpregu.00136.2019

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Folate And Vitamin D