Date of Award
11-16-2006
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Pharmacology, Physiology and Therapeutics
First Advisor
Joseph N. Benoit
Abstract
Chronic portal hypertension is an end-state clinical condition associated with cirrhosis and other diseases that elevate portal vascular resistance. An intriguing vascular consequence of chronic portal hypertension is impaired vasoconstrictor function which favors a chronically vasodilated condition. This vasoconstrictor dysfunction has been linked to prolonged activation of protein kinase A (PKA). However the cellular mechanism(s) responsible for the altered vasoconstrictor function is still not clear. The present studies tested my hypothesis that PKA mediates impaired vasoconstrictor function by affecting the actin filament dynamics via two small heat shock proteins, HSP20 and HSP27. Studies were conducted in isolated small mesenteric arteries and cultured vascular smooth muscle cells. I demonstrated reduced capacity of agonist-induced actin polymerization, increased HSP20 phosphorylation and decreased HSP20 expression in the portal hypertensive conditions. All are linked to the activation of PKA and are correlated with reduced maximal force development. By correlating MLC20 phosphorylation with actin polymerization in normal vessels, I demonstrated that MLC20 phosphorylation was necessary for actin polymerization. By introduction of the actin-binding domain of myosin head into β-escin permeabilized vessels, I demonstrated that myosin triggers actin polymerization in vascular smooth muscle. Subsequent studies indicated that HSP20 knockdown may specifically increase degradation of α-actin, leading to the suggestion that HSP20 regulates actin folding in smooth muscle. I conclude that HSP20 plays a role in the maintenance of the integrity of α-actin in vascular smooth muscle. I suggest that in chronic portal hypertensive condition, prolonged activation of PKA decreases HSP20 expression and impairs the integrity of α-actin, thereby reducing G-actin pools and limiting agonist-induced actin polymerization and force generation in vascular smooth muscle.
Recommended Citation
Chen, Xuesong, "Regulation Of Vascular Smooth Muscle Actin Polymerization: Pathophysiological Implications And Relations To Portal Hypertensive Conditions" (2006). Theses and Dissertations. 7966.
https://commons.und.edu/theses/7966