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 Ca 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 (LC) 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, LC, 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, LC, 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 Ca sensitization contributes to the dysfunctional cerebral myogenic response in the Goto-Kakizaki model of type 2 diabetes.

Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice With Metabolic Disease

“…This transition from compensatory increases in myogenic tone to autoregulatory failure has been observed in the type 2 diabetic Goto-Kakizaki rat, in that exaggerated pressure-induced contraction precedes loss of myogenic responses with ageing. 32–34 Impaired myogenic reactivity contributes to renal injury in the Dahl salt-sensitive rat 35 , whereas enhanced myogenic contractions and preserved renal function are found in the spontaneously hypertensive rat. 28 Similarly, in diabetic patients, loss of myogenic control is associated with the development of retinopathy.…”

Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

“…Recently, Abd-Elrahman et al reported that cerebral arteries isolated from T2D diabetic rats experienced an increased basal myogenic tone at low pressure points (1). They demonstrated that increased basal Rho-associated protein kinase (ROCK2) activity was responsible for the observed elevation in myogenic tone via inhibiting MLCP as well as mediating actin polymerization.…”

ROK and Arteriolar Myogenic Tone Generation: Molecular Evidence in Health and Disease

“…Although reduced myogenic constriction was reported in GK rats ( Kold-Petersen et al, 2012 ), longitudinal studies in cerebral arterioles of this model provided the molecular basis for the progressive loss of myogenic response from the prediabetic to the diabetic stage. Cerebral arterioles from these rats demonstrated an enhanced myogenic behavior during the prediabetic phase ( Abd-Elrahman et al, 2015a ). Specifically, enhanced LC20 phosphorylation and increased actin polymerization (lower G-actin level) occurred at low intraluminal pressure due to an increase in ROK activity rather than ROK protein expression.…”