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Conditioning Effect of Blood Flow on Resistance Artery Smooth Muscle Myosin Phosphatase

From the Department of Medicine (Cardiology) (H.Z., S.A.F.), Case Western Reserve School of Medicine, Cleveland, Ohio.

Correspondence to Steven A. Fisher, MD, Associate Professor of Medicine and Physiology, Case Western Reserve University School of Medicine, 422 BRB (LC 4958), 2109 Adelbert Road, Cleveland, OH 44106. E-mail saf9{at}po.cwru.edu

Myosin phosphatase is the primary effector of smooth muscle relaxation and a target of signaling pathways that regulate vascular tone. The mesenteric small resistance artery and large vessel smooth muscle express distinct isoforms of the myosin phosphatase targeting subunit (MYPT1), and the isoforms in the small resistance artery switch in a disease model of altered blood flow. We thus hypothesized that small resistance artery smooth muscle phenotype is responsive to altered blood flow. To test this hypothesis alternating pairs of rat second order mesenteric arteries were ligated so that the upstream first order mesenteric artery (MA1) is under chronic low flow and the adjacent first order mesenteric artery under chronic high flow. The initial response was similar in high flow and low flow MA1, and included rapid reduction in MYPT1 and switch to the 3' alternative exon skipped/leucine zipper positive MYPT1 isoform. Between 14 to 28 days, MYPT1 abundance was restored along with reversion to the MYPT1 leucine zipper^– isoform under chronic high flow. In contrast, under continued low flow, there was further switching to the MYPT1 leucine zipper⁺ isoform. As would be predicted based on the switch to the MYPT1 leucine zipper⁺ isoform, the sensitivity for relaxation to the NO donor SIN-1 and to cGMP was increased in the Day28 low flow first order mesenteric artery. We conclude that pulsatile blood flow conditions the phasic program of gene expression in the small resistance artery smooth muscle. The loss of this conditioning effect significantly increases the sensitivity to vasodilator signals in the setting of chronically reduced blood flow.

Key Words: myosin phosphatase • nitric oxide • cGMP • flow • resistance artery

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