Vitamin D Deficiency, Insulin Resistance and Cardiovascular disease

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ABSTRACT Nearly half of U.S adults have hypertension (HTN), a leading cause of the cardiovascular disease (CVD). HTN that develops earlier in life contributes to the early development of end-organ damage, thereby increasing the risk of cardiovascular mortality compared to later-onset HTN. Multiple studies provide evidence for the hypothesis that environmental factors in utero program patterns of fetal and infant growth that result in increased susceptibility to HTN later in life. Vitamin D (VD) deficiency is highly prevalent during pregnancy and has been linked to an increased risk of HTN during childhood. We previously found that macrophage-specific deletion of the VD receptor during early embryogenesis induced HTN by two mechanisms: a) renal-dependent by stimulating the secretion of miR106b to drive JG cell renin production and b) renal-independent by increased macrophage renin production and secretion. Additional studies in rodent models support the role of maternal VD deficiency in developing HTN and chronic inflammation via epigenetic mechanisms. In this proposal, we present preliminary data indicating for the first time that HTN is transplantable by immune cells. Hematopoietic stem cells (HSCs) from fetuses exposed to VD deficiency in utero can permanently transfer HTN to VD-sufficient adult mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1α pathway in HSCs, which persists in recipient bone marrow, resulting in macrophage renin and miR-106b secretion, both of which represent novel mechanisms by which immune cells contribute to the development of HTN. In humans, we found that this immune cells program causing HTN is preventable in children monocytes from the VDAART trial by antenatal 4400 IU/day of VD supplementation. Importantly, children from VD-supplemented mothers have decreased brachial-systolic blood pressure (BP). Thus, we hypothesize that VD supplementation early in pregnancy prevents epigenetic suppression of Jarid2 expression to avoid the BP-increasing effects of renin and miR106b secretion from myeloid cells. To evaluate this epigenetic immune program in vivo, we will utilize HSC transplantation models to determine in Aim1 if 1) Jarid2 deletion is sufficient to induce the HTN phenotype observed in the setting of in utero VD deficiency, 2) miR106b or renin deletion attenuates the HTN phenotype associated with in utero VD deficiency and 3) correction of VD deficiency early in pregnancy prevents the development of HTN in offspring. In Aim2, we will assess the role of maternal VD supplementation on VDAART children’s BP and monocyte Jarid2/PGC1α/Renin/miR106b pathway activation and determine if plasma miR106b and monocyte RAS activation are early markers of HTN in children at ages 9-11 from a randomized controlled trial (VDAART) of antenatal treatment with VD 4400 IU/d vs. placebo. This proposal will provide evidence for maternal early VD screening and treatment to decrease the incidence of childhood HTN and aim to establish miR106b as a specific biomarker identifying children at risk for CVD.