Regulation of Microvascular Function by ROS

Georgetown University, Washington DC

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Abstract

Low rates of Angiotensin II (Ang II) infusion increase reactive oxygen species (ROS), upregulate key renal[unreadable] components of NADPH oxidase (p22phox, NOX-1) and downregulate EC-SOD. Antioxidant drugs implicate[unreadable] ROS in the development of hypertension, yet the specific roles of renal and systemic ROS in[unreadable] vasoconstriction, salt retention and the mediation by NADPH oxidase, or by reduced SOD-dependent[unreadable] defense in the kidney, are largely undefined. We will study BP homeostasis (telemetric BP), salt handling[unreadable] and sensitivity and microvascular mechanisms in mice (isolated, perfused renal afferent and mesenteric[unreadable] resistance vessels and in vivo intravital microscopy) to explore the roles of an endothelium-derived[unreadable] contracting factor (EDCF) and enhanced VSMC contractility in the microvessels. We will relate these[unreadable] functional studies to ROS, NO, and calcium activity in individual microdissected vessels and pre-glomerular[unreadable] vascular smooth muscle cells. Our primary strategy is the use of knockout models and small interference[unreadable] RNAs (siRNAs) directed at target genes delivered intrarenally to assess specifically renal mechanisms of[unreadable] hypertension. This will be extended with kidney cross-transplantation combined with a cre-lox strategy to[unreadable] knockout genes specifically in VSMC to establish, for the first time, the roles of the kidney and its afferent[unreadable] arterioles in mediating hypertension with ROS. Aim 1 will use the EC-SOD -/- mouse model of stable, sustained microvascular oxidative stress to test the hypothesis that oxidative[unreadable] stress releases endothelin, which acts on type A or B receptors to engage a cyclooxygenase-derived EDCF[unreadable] that activates adjacent VSMCs where contractility is enhanced by a Ca++ sensitizing pathway mediated by[unreadable] rho/rho kinase. Aim 2 will use EC-SOD -/- mice administered siRNA to IC-SOD delivered selectively to the[unreadable] kidney to test the hypothesis that IC-SOD is the major antioxidant defense in the kidney and that its renal[unreadable] deficiency promotes renal vasoconstriction, salt retention, and hypertension. Aim 3 will use normal mice[unreadable] with siRNA to p22phox delivered to the kidney or systemically to test the hypothesis that renal NADPH[unreadable] oxidase mediates increased afferent arteriolar contractility, RVR, salt retention and hypertension with Ang II.[unreadable] These projects are an integrated approach to dissect the roles of ROS in renal microvascular reactivity and[unreadable] salt handling that constitute renal mechanisms of hypertension.