Myosin phosphatase isoforms in the microvasculature during endotoxemia (678.2)

Abstract

Sepsis is characterized by widespread inflammation and severe hypotension caused by the induction of iNOS as well as other vasodilators. We hypothesized that altered contractility of resistance artery smooth muscle could play a role in the later stages of sepsis. Sepsis was modeled via a single IP injection of lipopolysaccharides (LPS; 20mg/kg), and mouse vascular tissues were harvested 24hrs post injection. We examined the expression of the myosin phosphatase (MP) regulatory (Mypt1) and inhibitory (CPI‐17) subunits. Expression of Mypt1 Exon24/leucine zipper variants may determine sensitivity to vasodilator NO, while the level of expression of CPI‐17 may determine sensitivity to vasoconstrictor NE. Mesenteric and femoral arteries and portal veins switched from the E24+/LZ‐ isoform to the E24‐/LZ+ isoform of Mypt1 (p<0.05) with decreases in total Mypt1 and CPI‐17 transcript expression (p<0.05). Relaxation to cGMP via wire myography was enhanced in α‐toxin permeabilized mesenteric arteries from LPS injected mice compared to saline injected control. Constriction to phenylephrine activation was significantly depressed in LPS injected mice compared to control. We propose that endotoxemia triggers specific changes in MP subunit expression thereby enhancing vasodilatory mechanisms and suppressing vasoconstrictor mechanisms thereby contributing to the severe hypotension of the later stages of sepsis.Grant Funding Source: HL066171