UC Riverside

Chronic vascular inflammation is a hallmark of various debilitating conditions such as atherosclerosis, diabetes, and emphysema. Although these conditions are marked by abnormal vascular stiffness, whether and how it contributes to vascular inflammation has largely remained unknown. The goal of this research was to address this vital gap in our mechanistic understanding of chronic vascular inflammation. Since vascular stiffness is a manifestation of subendothelial matrix stiffness and EC function is known to be regulated by matrix stiffness, the central hypothesis of this research was that abnormal subendothelial matrix stiffness alters EC mechanotransduction that, in turn, enhances EC adhesivity and leukocyte-EC adhesion, rate-limiting steps in chronic vascular inflammation. Findings from the current research revealed that ECs grown on very soft or stiff matrices elicit significantly greater monocyte adhesion that, in turn, is mediated by a preferential increase in Rho-mediated clustering of endothelial intercellular cell adhesion molecule-1 (ICAM-1) on these matrices. Subsequent mechanistic studies showed that increased monocyte-EC adhesion on stiffer subendothelial matrices results from loss of transient receptor potential vanilloid 4 (TRPV4), a calcium ion channel that enhances the formation of endothelial nitric oxide, a Rho inhibitor. These in vitro data are supported by in vivo observations that endothelial TRPV4 is downregulated in the stiffer, inflamed aortas of atherosclerotic (ApoE-/-) and diabetic (db/db) mice. To further identify the upstream regulators of endothelial TRPV4 that contribute to EC adhesivity, the role of microRNAs (miR) was examined in an in vitro model of diabetic vascular inflammation. MicroRNAs are small non-coding RNA (~20–22 nucleotides) that mediate epigenetic control of gene expression. These studies showed that microRNA 203a (miR-203a), which targets TRPV4, is upregulated under high glucose conditions, resulting in TRPV4 downregulation and associated loss of endothelial nitric oxide and increased monocyte-EC adhesion. Importantly, suppression of miR-203a and the concomitant increase in TRPV4 prevented the inflammatory effects of high glucose on ECs. Taken together, these novel findings not only elucidate a key role of matrix stiffness, mechanosensitive TRPV4, and upstream epigenetic mechanisms in regulating EC adhesivity associated with chronic vascular inflammation but, crucially, identify potentially new targets (e.g. TRPV4, miR-203a) for more effective anti-inflammatory therapies in the future.