P21‐activated kinase inhibits vascular reactivity via inhibition of MLCK

Abstract

Changes in vascular reactivity contribute to the pathology of a number of different diseases including heart failure, hypertension, severe trauma, and sepsis. P21‐activated kinase (PAK) can alter smooth muscle contractile activity and has been implicated in altering vascular reactivity. The objective of this study was to determine the mechanism by which PAK regulates MLC phosphorylation in vascular smooth muscle to alter vascular reactivity. The effects of PAK activation and inhibition on basal and agonist‐induced aortic contraction in aortic rings and on myosin light chain (MLC) and myosin targeting subunit of MLC phosphatase (MYPT1) phosphorylation and MLC kinase (MLCK) activity in primary aortic smooth muscle cells (ASMC) were determined. Finally, the effects of increased mechanical stimulation on PAK activation were determined in ASMC. PAK activation inhibited both basal tone and agonist induced contraction of rat aortic rings. Conversely, PAK inhibition increased agonist induced contraction and basal tone. In ASMC, PAK activation inhibited MLC phosphorylation and PAK inhibition increased MLC phosphorylation. However, PAK activation increased MYPT1 phosphorylation in ASMC. Increased mechanical stimulation of ASMC increased PAK activation and decreased MLCK activation. These data suggest that PAK inhibits vascular reactivity via decreased inhibition of MLCK.