Redox Switches Controlling Nitric Oxide Signaling in the Resistance Vasculature and Implications for Blood Pressure Regulation: Mid-Career Award for Research Excellence 2020

Abstract

The arterial resistance vasculature modulates blood pressure and flow to match oxygen delivery to tissue metabolic demand. As such, resistance arteries and arterioles have evolved a series of highly orchestrated cell-cell communication mechanisms between endothelial cells and vascular smooth muscle cells to regulate vascular tone. In response to neurohormonal agonists, release of several intracellular molecules, including nitric oxide, evokes changes in vascular tone. We and others have uncovered novel redox switches in the walls of resistance arteries that govern nitric oxide compartmentalization and diffusion. In this review, we discuss our current understanding of redox switches controlling nitric oxide signaling in endothelial and vascular smooth muscle cells, focusing on new mechanistic insights, physiological and pathophysiological implications, and advances in therapeutic strategies for hypertension and other diseases.

S1P (Sphingosine-1-Phosphate)–Induced Vasodilation in Human Resistance Arterioles During Health and Disease

“…Maintaining normal blood pressure requires tight control of arterial tone predominantly in the resistance arterioles, a subtype of blood vessels that regulate peripheral vascular resistance. Resistance within arterioles, or microvascular tone, is modulated by various stimuli including shear-induced vasoactive mediators such as NO, 1 hydrogen sulfide, 2 and reactive oxygen species (ROS), such as H 2 O 2 , 3 to name a few. Although many vasoactive compounds exist that freely diffuse out of the endothelium to relax surrounding smooth muscle, NO production via eNOS (endothelial nitric oxide synthase or NOS3 [nitric oxide synthase 3]) is preferred due to its anti-inflammatory properties on surrounding tissues as opposed to the damaging effects of H 2 O 2 .…”

Mitochondrial Dysfunction: An Emerging Link in the Pathophysiology of Cardiorenal Syndrome

“…Moreover, experimental evidence suggests the activities of superoxide dismutase, catalase, and glutathione peroxidases are significantly reduced during HF (17). Mitochondria-targeted ROS scavenging (e.g., MitoQ, MitoTEMPO, or SS-31) has demonstrated benefit in animal models of HF (57)(58)(59). Interestingly, NAD + , a precursor for the phosphorylated dinucleotide pair NADP + /NADPH (plays a major role in the detoxification of ROS), was also significantly reduced in the myocardium of some HF mice (60).…”