Approximately 1 billion individuals worldwide suffer from hypertension, making it one of the most common chronic disorders (1). Concomitantly, hypertension is an independent risk factor for cardiovascular and cerebrovascular disorders, harms quality of life, and is the leading cause of premature mortality globally (2). Nevertheless, due to the under diagnosis and under treatment of hypertension, the rates of blood pressure (BP) control remain poor and far from satisfactory worldwide. To reduce premature mortality, prevention and control of hypertension is an essential global public health strategy (3).

As a fat-soluble steroid hormone, vitamin D is essential for calcium and phosphorus balance and bone health. In addition to dietary intake, subcutaneous endogenous synthesis is an alternative major source of vitamin D. Vitamin D first must be hydroxylated to 25-hydroxyvitamin in the liver and further to 1,25-dihydroxyvitamin in the kidney enabling bioavailability (4). Interestingly, vitamin D receptors and the vitamin D enzyme system have been discovered to exist in the majority of cells in the body, with the ability to drive the transcription of hundreds of genes (5). Therefore, many scholars reasonably hypothesize that vitamin D may affect human health more than its role in bone health. To date, extensive published studies have described that vitamin D deficiency is related to osteoporosis, cancer, cardiovascular diseases, type 2 diabetes, inflammation, and autoimmune diseases (4, 5). Regretfully, large randomized controlled trials have not found convincing evidence that supplementing with vitamin D helps prevent certain disorders, such as hypertension. Moreover, existing studies have a few limitations, such as small sample sizes, insufficient adjustment of some important covariates, and specific participants. In addition, whether complications could modify the association of interest remains unclear.

In the current study, we attempted to investigate the relationships between serum 25(OH)D and BP, detailing systolic and diastolic blood pressure, in a nationally representative sample of US adults with no previous diagnosis of hypertension.

Our analyses, based on a nationally representative population from seven consecutive NHANES cycles (2005–2018), were performed to explore the relationship between serum 25(OH)D concentrations and BP in adults with no previous diagnosis of hypertension in the US. The key findings could be summarized in three points. First, after adjusting multiple variables, serum 25(OH)D was negatively correlated with BP, primarily SBP. Second, the relationships between serum 25(OH)D concentration and BP, including SBP and DBP, were non-linear. Third, the relationship was consistent across the subgroups except for sleeplessness.

Early in the 1980s, Sowers et al. (8) discovered a significant negative relationship between ingestion of vitamin D and BP. In the following decades, cross-sectional studies based on the Third National Health and Nutrition Examination Survey (NHANES III) have obtained the same conclusions (9, 10). However, prospective cohort studies elicited inconsistent results. After 4 years of follow-up, Forman et al. (11) found that compared with women without vitamin D deficiency [25(OH)D <15 ng/ml], women with vitamin D deficiency had a multivariable relative risk (RR) of 2.98 (95% CI: 1.24 to 7.20). Moreover, the risk was even more markedly elevated among men with vitamin D deficiency. Nonetheless, after an 8-year follow-up period, the RRs for hypertension incidents had reduced and were no longer statistically significant. It is noteworthy that there are only 33 participants with 25(OH)D deficiency in this study, so the representativeness of its outcomes needs to be queried. In the Tromsø study conducted by Jorde et al. (12), they proceeded with a 14-year follow-up from 1994 to 2008. They observed that, after controlling variables, serum 25(OH)D in 1994 failed to predict future hypertension or increased BP, and that there was no significant relationship between changes in serum 25(OH)D and changes in BP from 1994 to 2008. Moreover, various researchers had further investigated the relationship between vitamin D supplementation and lowering BP, obtaining negative (13–17) and positive (18–21), seemingly contradictory results, which brought into doubt the prospects of vitamin D for lowering BP. But previous studies had some limitations: small sample size (11), not taking into account some important covariates (such as chronic disease (9, 10, 12), smoking/drinking (10, 11), dietary supplement use (9, 11, 12), etc., which could significantly influence serum 25(OH)D status and prevalence of hypertension), specific participants population. However, our research was a significant cross-sectional study and employed a nationally representative sample of US adults, excluding those taking hypotensive drugs or history of physician-diagnosed hypertension participants to minimize the likelihood that they improve their BP through lifestyle changes and agents. At the same time, we adjusted for lifestyle habits, comorbidities, and serological indicators and further analyzed the effect of serum 25(OH)D concentration on systolic and diastolic blood pressure, respectively. Consistent with the previous cross-sectional studies, we found a negative relationship between serum 25(OH)D levels and higher BP. At the same time, our study further revealed that higher serum 25(OH)D levels were associated with lower SBP. As for the contribution between serum 25(OH)D levels and DBP, there was even a positive effect, but it was not statistically significant.

So far, the exact mechanism of hypotension by serum 25(OH)D is still unknown, and there are several possible core factors. An animal experiment conducted by Li et al. (22) found a several-fold increase in renin expression and plasma angiotensin II production in mice with vitamin D receptor-null (VDR-null). Thus, it gave rise to the earliest and currently widely accepted mechanism that vitamin D can lower BP by suppressing renin synthesis to downregulate the activity of the renin-angiotensin-aldosterone system (RASS) (23). Moreover, vitamin D inhibits the production of parathyroid hormone (PTH), which can increase BP by stimulating PTH2 receptors expressed on vascular smooth muscle cells, upregulating both receptors of advanced glycation end products (RAGE) expression and monocyte-macrophages cytokines and IL-6 production, and promoting the deposition of calcium in the arterial wall leading to increasing collagen deposition and vessel stiffness (24). These imply that lack of vitamin D may be a risk factor for hypertension. In our study, when serum 25(OH)D <85 nmol/L, it was negatively correlated with SBP but not with DBP. A cross-sectional study of the biethnic population discovered that SBP was inversely associated with 25(OH)D levels in whites but not in blacks (25). Later on, Jafari et al. (26) conducted a meta-analysis of 26 randomized controlled trials for patients with diabetes and demonstrated that vitamin D improved SBP in type 2 diabetic patients. Subsequent studies have revealed similar findings (27–29), but few studies have been conducted in patients without hypertension, and our experiment fills this gap. It is well known that BP is defined as the lateral pressure exerted on the walls of blood vessels per unit area during the flow of blood (3). Part of the stroke volume is sent directly to peripheral tissues during ventricular contraction, resulting in systolic pressure, while part of it is temporarily stored in the aorta and central artery, stretching the arterial wall and rising local BP, resulting in diastolic pressure (30). BP is directly influenced by two primary factors: the volume of intravascular fluid and the capacity for vasodilation. As previously mentioned, vitamin D can downregulate the activity of the RASS, which exerts various physiological and pathophysiological effects including vasoconstriction and sodium/water retention to elevate BP via activation of angiotensin II type 1 receptor (AT1R). In addition, when vitamin D deficiency induces vascular sclerosis and stretching disturbances, the entire stroke volume flows through the arterial system and peripheral tissues, which results in increased SBP and decreased DBP (30). Further investigations of the antihypertensive mechanism of vitamin D are now warranted.

Increasing evidence supports the existence of a threshold effect for vitamin D levels (31). In our study, as mentioned previously, the relationship of vitamin D with higher blood pressure and higher SBP was U- and L-shaped, respectively. Furthermore, both of them had a cut-off value of approximately 84 nmol/L. For higher blood pressure, the risk was increased for both vitamin D levels below or above 84 nmol/L. The risk of higher SBP rose significantly below 84 nmol/L but remained marginally significant above 84 nmol/L. These outcomes indicated that subjects with vitamin D insufficiency or deficiency were more sensitive to vitamin D supplementation, and there was a risk of higher blood pressure, primarily DBP, when vitamin D is above 84 nmol/L. In support, previous studies also showed that the antihypertensive effect of vitamin D supplementation was observed only in patients with vitamin D insufficiency or deficiency (21, 32–34). However, to the best of our knowledge, a particular Z-shaped relationship between serum 25(OH)D and DBP was detected for the first time. It revealed a negative relationship between serum 25(OH)D and DBP within the range of 36 to 84 nmol/L but a positive relationship below or above the range.

Upon further subgroup analysis, we found that the inverse association between serum 25(OH)D and BP tends to be more pronounced and sustained among participants with sleeplessness. As well, recently, a cross-sectional study showed a more pronounced and stable association between vitamin D status and coronary heart disease in participants with poor sleep patterns (35). As far as we know, sleeplessness is recognized as short sleep duration and insomnia, and daytime sleepiness may be linked to reduced outdoor exercise and sunlight exposure, which may diminish serum vitamin D via endogenous synthesis (36, 37) and boost melatonin expression (38). As a result, subjects with sleeplessness had lower levels of serum vitamin D compared with those without sleeplessness, so the decline in blood pressure resulting from serum vitamin D levels was more evident according to our findings. However, further studies are needed to validate these findings.

It is important to note that there are some limitations in our study. First, there is a dearth of data on participants' salt intake and sun exposure, which are important factors in endogenous vitamin D production and hypertension, respectively. Second, we performed a single measurement of plasma 25(OH)D, which had a marked circadian variation. Third, because BP was measured merely in a single appointment, it is possible that some participants were wrongly labeled as having higher blood pressure while they were actually normotensive, and vice versa. Fourth, biases resulting from excluded and unmeasured confounders may still exist, despite our efforts to account for as many confounders as possible. Fifth, relationships between 25(OH)D and BP stratified by sleeplessness deserve to be further verified. Finally, the cross-sectional design also makes it impossible to distinguish between causes and effects.

We discovered a non-linear association between serum 25(OH)D concentration and BP in a nationally representative sample of US participants without a previous diagnosis of hypertension. Concentrations of 25(OH)D were inversely associated with blood pressure when it was <84 nmol/L. More specifically, serum 25(OH)D is adversely correlated with systolic blood pressure, and as for diastolic blood pressure, higher serum 25(OH)D concentrations were associated with higher diastolic blood pressure when serum 25(OH)D levels >84 nmol/L.

Publicly available datasets were analyzed in this study. This data can be found here: https://www.cdc.gov/nchs/nhanes/index.htm.

The studies involving human participants were reviewed and approved by the National Center for Health Statistics Research Ethics Review Board. The patients/participants provided their written informed consent to participate in this study.

JC: Writing—original draft, Investigation, Validation. JT: Validation, Writing—original draft. XK: Data curation, Formal analysis, Writing—review and editing. CZ: Data curation, Formal analysis, Writing—review and editing. RZ: Visualization, Writing—review and editing. JS: Visualization, Writing—review and editing. XZ: Visualization, Writing—review and editing. ZL: Conceptualization, Writing—review and editing.