title: Abnormal myosin phosphatase targeting subunit 1 phosphorylation and actin polymerization contribute to impaired myogenic regulation of cerebral arterial diameter in the type 2 diabetic Goto-Kakizaki rat.
abstract: The myogenic response of cerebral resistance arterial smooth muscle to intraluminal pressure elevation is a key physiological mechanism regulating blood flow to the brain. Rho-associated kinase plays a critical role in the myogenic response by activating Ca2+sensitization mechanisms: (i) Rho-associated kinase inhibits myosin light chain phosphatase by phosphorylating its targeting subunit myosin phosphatase targeting subunit 1 (at T855), augmenting 20 kDa myosin regulatory light chain (LC20) phosphorylation and force generation; and (ii) Rho-associated kinase stimulates cytoskeletal actin polymerization, enhancing force transmission to the cell membrane. Here, we tested the hypothesis that abnormal Rho-associated kinase-mediated myosin light chain phosphatase regulation underlies the dysfunctional cerebral myogenic response of the Goto-Kakizaki rat model of type 2 diabetes. Basal levels of myogenic tone, LC20, and MYPT1-T855 phosphorylation were elevated and G-actin content was reduced in arteries of pre-diabetic 8-10 weeks Goto-Kakizaki rats with normal serum insulin and glucose levels. Pressure-dependent myogenic constriction, LC20, and myosin phosphatase targeting subunit 1 phosphorylation and actin polymerization were suppressed in both pre-diabetic Goto-Kakizaki and diabetic (18-20 weeks) Goto-Kakizaki rats, whereas RhoA, ROK2, and MYPT1 expression were unaffected. We conclude that abnormal Rho-associated kinase-mediated Ca2+sensitization contributes to the dysfunctional cerebral myogenic response in the Goto-Kakizaki model of type 2 diabetes.
authors.affiliation: The Smooth Muscle Research Group, Departments of Physiology & Pharmacology, Libin Cardiovascular Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Khaled S
authors.initials: KS
authors.lastname: Abd-Elrahman
authors.affiliation: The Smooth Muscle Research Group, Departments of Physiology & Pharmacology, Libin Cardiovascular Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Olaia
authors.initials: O
authors.lastname: Colinas
authors.affiliation: The Smooth Muscle Research Group, Departments of Physiology & Pharmacology, Libin Cardiovascular Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Walsh
authors.affiliation: The Smooth Muscle Research Group, Departments of Physiology & Pharmacology, Libin Cardiovascular Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Hai-Lei
authors.initials: HL
authors.lastname: Zhu
authors.affiliation: The Smooth Muscle Research Group, Departments of Physiology & Pharmacology, Libin Cardiovascular Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Campbell
authors.affiliation: The Smooth Muscle Research Group, Department of Biochemistry & Molecular Biology, Libin Cardiovascular Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walsh
authors.affiliation: The Smooth Muscle Research Group, Departments of Physiology & Pharmacology, Libin Cardiovascular Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada wcole@ucalgary.ca.
authors.forename: William C
authors.initials: WC
authors.lastname: Cole
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002536:Cerebral Arteries / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D043263:Myosin-Light-Chain Phosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D058105:Polymerization; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction; D054460:rho-Associated Kinases
chemical_list: D000199:Actins; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; D002118:Calcium
keywords: Ca2+ sensitization; Goto-Kakizaki; Rho-associated kinase; cerebral arteries; type 2 diabetes