Drs Yuping Wang and David F. Lewis from Louisiana State University Health Sciences Center – Shreveport, discuss the impact of vitamin D deficiency and aberrant vitamin D receptor expression on endothelial function in preeclampsia
Preeclampsia is a hypertensive disorder in human pregnancy. It is characterised by increased maternal blood pressure and signs of damage to other organ systems, most often the kidneys and liver. This pregnancy disorder is not only a leading cause of maternal and foetal morbidity and mortality in pregnancy, but also a recognised risk factor for cardiovascular diseases (CVDs) in women later in life.
Endothelium plays critical roles in maintaining vascular health
The endothelium has distinct functions in vascular biology: producing vasoactivators to regulate blood flow and vascular tone; acting as a semi-selective barrier to limit materials and circulating cells passing into and out of the bloodstream; providing a non-thrombogenic surface to limit platelet aggregation and control coagulation cascade; and generating angiogenic factors to repair vessel injury, etc.
Importantly, vascular endothelium has endogenous anti-inflammatory machinery to control the pro-inflammatory mediator-induced inflammatory response in the vascular system. This machinery includes platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), endothelial nitric oxide synthase (eNOS), and suppressor of cytokine signaling-3 (SOCS-3), etc.
PECAM-1 and eNOS can inhibit leukocyte activation, suppress pro-inflammatory cytokine production, and maintain vascular barrier integrity. SOCS-3 is a member of the suppressor of cytokine signaling (SOCS) family and functions as a cytokine-inducible negative regulator of cytokine signaling, especially controls IL-6-induced inflammatory response to against inflammatory insult in the vascular system.
Vascular dysfunction in preeclampsia
Although improper immune adaptation and poor placentation are believed to be the early events in preeclampsia development, maternal vascular endothelium appears to be the critical target of the placental-derived factors that extend the systemic vascular dysfunction in preeclampsia. Increased maternal inflammatory cytokine IL-6, IL-8, IL-16, and TNFα levels, increased leukocyte-endothelial interaction/adhesion and platelet aggregation, and increased endothelial permeability are hallmarks of endothelial dysfunction and enhanced endothelial inflammatory response in preeclampsia. Increased endothelial inflammatory response is also evidenced by reduced anti-inflammatory mediators PECAM-1, eNOS, and SOCS-3 expression in the maternal vascular system.
In addition, increased oxidative stress, reduced vasodilator production, and imbalanced immune cell activities, etc. are all directly linked to the increased endothelial inflammatory response in preeclampsia. The excessive inflammatory response changes endothelial physiology and integrity, subsequently, leading to various degrees of endothelial dysfunction in preeclampsia.
Vitamin D deficiency and aberrant VDR expression
In the past decade, mounting evidence has shown that vitamin D plays an important role in pregnancy. Other than maintaining bone health, reducing oxidative stress, and promoting foetal development, one vital function of bioactive vitamin D, 1,25(OH)2D, is to modulate the immune system and inflammatory response. 1,25(OH)2D achieves its bioactivity through binding to its receptor, vitamin D receptor (VDR).
VDR, the ligand-activated transcriptional factor, will then bind to vitamin D response element (VDRE) in the promoter region of the target gene, subsequently induce a serial of cellular and molecular reactions. Therefore, availability of VDR determines the downstream 1,25(OH)2D actions. However, their recent finding demonstrated that VDR expression is markedly downregulated in the maternal vascular endothelium in preeclampsia.1
Although the reason for reduced VDR expression is not known, since VDR expression is inducible in endothelial cells2 and maternal vitamin D levels are reduced in preeclampsia, lack of ligand stimulation due to low maternal circulating vitamin D levels could explain, at least in part, reduced VDR expression in the vascular system in preeclampsia.
To study how low maternal vitamin D levels and reduced VDR expression are associated with an increased endothelial inflammatory response in preeclampsia, their team specifically looked into the connection of VDR with miR-126 and VCAM-1 expression in maternal systemic vessels from normal and preeclamptic pregnant women. miR-126 is an endothelial-specific microRNA that regulates angiogenesis and exerts anti-inflammatory activity. VCAM-1 mediates the adhesion of leukocytes to vascular endothelium and functions in leukocyte-endothelial signaling transduction. VCAM-1 is also involved in the development of atherosclerosis and increased VCAM-1 expression is an indicator of the cytokine-induced increased inflammatory response in endothelial cells. VCAM-1 is a target of miR-126.
Very interestingly, they found that upregulation of VCAM-1 expression was associated with downregulation of miR-126 expression in maternal vessel endothelium in preeclampsia.1 In an in vitro cell culture model, they demonstrated that TNFα-induced increase in endothelial VCAM-1 expression and production could be suppressed when miR-126 was overexpressed in cells. Strikingly, TNFα-induced increase in endothelial VCAM-1 expression could also be suppressed by exposing cells to 1,25(OH)2D. Their results indicate that both miR-126 and 1,25(OH)2D exert anti-inflammatory activity in endothelial cells. To test the association of 1,25(OH)2D and miR-126, they found that 1,25(OH)2D could induce a dose-dependent increase in miR-126 production in endothelial cells.
Using VDR siRNA, they further demonstrated that 1,25(OH)2D induced upregulation of miR-126 was mediated by VDR. In addition to miR-126, their data also showed that 1,25(OH)2D could prevent TNFα-induced downregulation of SOCS-3 expression and sustain eNOS expression under oxidative stress stimulation in endothelial cells.1,3 In preeclampsia, reduced SOCS-3 expression in maternal vessels is associated with increased circulating IL-6 levels.4 These results suggest that 1,25(OH)2D induced miR-126 production, and maintenance of SOCS-3 and eNOS expression could be a potential mechanism of 1,25(OH)2D anti-inflammatory activity in the vascular system.
Preeclampsia and CVDs in women later in life
Many studies have shown that the incidence of CVDs is increased in women who had preeclampsia compared to those are not. Chronic increased inflammatory response in women after preeclampsia was also reported as evidenced by elevated circulating cytokine IL-6/IL-10 ratio.5 Vitamin D deficiency has been linked to increased inflammatory responses in many disease conditions, including preeclampsia and hypertension, and vitamin D deficiency is a risk factor for CVDs and Type 2 diabetes. If low vitamin D levels and reduced VDR activity persist in the vascular system in women after preeclampsia, there is no doubt that reduced anti-inflammatory activity due to vitamin D deficiency and lack of VDR expression would increase the risk for the development of CVDs. Therefore, vitamin D sufficiency during pregnancy is expected to have long-term beneficial effects in women later in life.
References
- Xu J, Gu Y, Lewis DF, Cooper DB, McCathran CE, Wang Y. Downregulation of VDR and miR-126-3p expression contributes to increased endothelial inflammatory response in preeclampsia. Am J Reprod Immunol. 2019; 82(4): e13172.
- 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. 2014; 140: 56-62.
- Jia X, Xu J, Gu Y, Gu X, Li W, Wang Y. Vitamin D suppresses oxidative stress-induced microparticle release by human umbilical vein endothelial cells. Biol Reprod. 2017; 96: 199-210.
- Wang Y, Lewis DF, Gu Y, Zhao S, Groome LJ. Elevated maternal soluble gp130 and IL-6 levels and reduced gp130 and SOCS-3 expressions in women with preeclampsia. Hypertension. 2011; 57: 336-342.
- Freeman DJ, McManus F, Brown EA, Cherry L, Norrie J, Ramsay JE, Clark P, Walker ID, Sattar N, Greer IA. Short- and long-term changes in plasma inflammatory markers associated with preeclampsia. Hypertension. 2004; 44: 708-714.
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