The Molecular Basis for Impaired Cerebral Myogenic Response in Type 2 Diabetes
Date
2015-04-06
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Abstract
Cognition and brain function are dependent on appropriate control of blood flow within the cerebral circulation. Cerebral blood flow is controlled through the interplay of several physiological mechanisms that regulate the contractility of vascular smooth muscle cells (VSMCs) within the wall of cerebral arteries. The myogenic response of cerebral arteries is a crucial mechanism that is responsible for maintaining adequate brain blood flow. This fundamental mechanism is due to cellular processes intrinsic to VSMCs including: 1) Ca2+-calmodulin-dependent activation of myosin light chain kinase and phosphorylation of LC20, 2) Rho-associated kinase (ROK)-dependent phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and suppression of myosin light chain phosphatase activity, and 3) dynamic reorganization of the actin cytoskeleton. Inappropriate regulation of one or more of these mechanisms may contribute to the dysfunctional control of cerebral diameter and flow, predisposing type 2 diabetic patients to ischemic and hemorrhagic stroke. Here, we employed Goto-Kakizaki (GK) rats, a type 2 diabetic rat model, to identify the molecular basis for the dysfunctional myogenic constriction in early and established type 2 diabetes. We detected an enhanced basal myogenic tone in prediabetic GK cerebral arteries at low intraluminal pressure that progressed with the severity of diabetes such that the myogenic response was lost in arteries of GK rats with established diabetes. Our biochemical evidence shows that there are parallel, progressive alterations in MYPT1 and LC20 phosphorylation, as well as actin polymerization downstream of ROK that are consistent with the evolution of dysfunctional myogenic response. These findings provide a better understanding of the underlying defects responsible for dysfunctional control of cerebral arterial diameter and blood flow in type 2 diabetes.
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Biology--Molecular, Physiology, Pharmacology
Citation
Abdelrahman, K. (2015). The Molecular Basis for Impaired Cerebral Myogenic Response in Type 2 Diabetes (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28249