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1 Department of Medicine and Physiology, Case Western Reserve University, Cleveland, OH, USA
2 Department of Pharmacology, Physiology & Therapeutics, University of North Dakota, Grand Forks, ND, USA
3 Department of Physiology, Univesity of Massachusetts, Worcester, MA, USA
* To whom correspondence should be addressed. E-mail: saf9{at}po.cwru.edu.
Myosin phosphatase is a target for signaling pathways that modulate the calcium sensitivity of force production in smooth muscle. Isoforms of the myosin phosphatase targeting subunit 1 (MYPT1) are generated by cassette-type alternative splicing of exons in the central and 3' portion of the transcript. The exclusion of the 3'alternative exon, coding for the leucine zipper positive isoform of MYPT1, is associated with the ability to de-sensitize to calcium (relax) in response to NO/cGMP-dependent signaling. Here we examined the expression of the MYPT1 isoforms and smooth muscle phenotype in vessels of normal rats and in a pre-hepatic model of portal hypertension characterized by arteriolar dilation. The large capacitance vessels, the aorta, pulmonary artery, and inferior vena cava expressed predominantly the 3' exon out/ leucine zipper positive isoform of MYPT1. The first order mesenteric resistance artery and portal vein expressed several-fold higher levels of MYPT1 with predominance of the 3' exon included/leucine zipper negative isoform. There was minor variation in the presence of the MYPT1 central alternative exons. Myosin heavy and light chain splice variants in part cosegregated with the MYPT1 isoforms. In response to portal hypertension induced by PV ligature, the abundance of MYPT1 in the portal vein and MA1 was significantly reduced and switched to the leucine zipper positive isoform. These changes were evident within 1 day of PV ligature and were maintained for up to 10 days before reverting to control values at day 14. The alteration of MYPT1 expression was part of a complex change in protein expression that can be generalized as a modulation from a phasic (fast) to tonic (slow) contractile phenotype. The implications of vascular smooth muscle phenotypic diversity and reversible phenotypic modulation in portal hypertension with regards to the regulation of blood flow are discussed.
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