Hypertension is a multi-system disease. Commensal bacteria that inhabit the gut (gut microbiome) can affect vascular tone and modulate blood pressure. Normotensive animals become hypertensive when transplanted with gut microbiota from hypertensive animals, and vice versa. Furthermore, hypertension in humans is associated with specific alterations in gut microbial diversity, lending credence to the premise that a change in gut microbial load and diversity (dysbiosis) contributes to the pathogenesis of hypertension. This application lies at the intersection of gut dysbiosis and hypertension. It posits that gut dysbiosis is a key driver of increased vascular tone in hypertension It also puts forth the hypothesis that vascular smooth muscle-enriched microRNA-204 (miR-204) relays metabolic signals originating from gut bacteria to control smooth muscle contraction via its effects on sarcoplasmic reticulum Ca2+ release into the cytoplasm. The application is supported by strong preliminary data. It shows a change in the gut microbial community, and microbe-derived metabolites, in hypertensive mice. It further shows that antibiotic-induced gut dysbiosis in mice downregulates vascular smooth muscle miR-204, leads to hypercontractility of blood vessels, is associated with upregulation of Inositol 1,4,5- trisphosphate (IP3) receptor (IP3R1) which controls vascular smooth muscle cytosolic Ca2+, and deregulates vascular smooth muscle intracellular Ca2+ homeostasis. This application is highly novel, mechanistic as well as potentially translatable. It will leverage unique tissue-targeted genetically modified mice, and in vitro tools, to dissect the relationship between miR-204, the gut microbiome, and the sarcoplasmic reticulum Ca2+ apparatus in vascular smooth muscle cells. In addition, it will use state-of-the-art methodologies to assess Ca2+ flux in cells and in vessels of live animals. Finally, it will explore whether bacterial metabolites can reverse deregulation of Ca2+ homeostasis and mitigate the development of hypertension. Given the enormous interest in how the human microbiome impacts health and disease, this application provides a unique opportunity to explore how a microRNA regulated by gut bacteria modulates blood pressure. Such information will open the door for microRNA-based and/or microbiota-based therapeutics to prevent or treat hypertension.
The significance of this proposal is driven by the potential impact of identifying novel therapies to enhance the cardiovascular function during hypertension. We will explore gut microbiota and miR-204 as potential cardiovascular- therapeutic agents, evaluating their effect on vascular calcium and vascular smooth muscle cells (VSMC) function. Understanding the mechanism by which microbiota and miR-204 mediates vascular caclium disruption and VSMC dysfunction may lead to novel treatment strategies conferring the benefits of calcium control while circumventing the potential risks of delivering live biologics.
