Faculty Collaboration Database

Modulation of p66Shc impairs cerebrovascular myogenic tone in low renin but not low nitric oxide models of systemic hypertension. Am J Physiol Heart Circ Physiol 2021 Dec 01;321(6):H1096-H1102

Date

10/30/2021

Pubmed ID

34714691

Pubmed Central ID

PMC8834231

DOI

10.1152/ajpheart.00542.2021

Scopus ID

2-s2.0-85120604529 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

Cerebral blood flow and perfusion are tightly maintained through autoregulation despite changes in transmural pressure. Oxidative stress impairs cerebral blood flow, precipitating cerebrovascular events. Phosphorylation of the adaptor protein p66Shc increases mitochondrial-derived oxidative stress. The effect of p66Shc gain or loss of function in nonhypertensive rats is unclear. We hypothesized that p66Shc gain of function would impair autoregulation of cerebral microcirculation under physiological and pathological conditions. Three previously established transgenic [salt-sensitive (SS) background] p66Shc rats were used, p66-Del/SS (express p66Shc with a nine-amino acid deletion), p66Shc-knockout (KO)/SS (frameshift premature termination codon), and p66Shc signaling and knock-in substitution of Ser36Ala (p66Shc-S36A)/SS (substitution of Ser36Ala). The p66Shc-Del were also bred on Sprague-Dawley (SD) backgrounds (p66-Del/SD), and a subset was exposed to a hypertensive stimulus [N^G-nitro-l-arginine methyl ester (l-NAME)] for 4 wk. Active and passive diameters to increasing transmural pressure were measured and myogenic tone was calculated in all groups (SS and SD). Myogenic responses to increasing pressure were impaired in p66Shc-Del/SS rats relative to wild-type (WT)/SS and knock-in substitution of Ser36Ala (S36A; P < 0.05). p66-Del/SD rats did not demonstrate changes in active/passive diameters or myogenic tone relative to WT/SD but did demonstrate attenuated passive diameter responses to higher transmural pressure relative to p66-Del/SS. Four weeks of a hypertensive stimulus (l-NAME) did not alter active or passive diameter responses to increasing transmural pressure (P = 0.86-0.99), but increased myogenic responses relative to p66-Del/SD (P < 0.05). Collectively, we demonstrate the functional impact of p66Shc within the cerebral circulation and demonstrate that the genetic background of p66Shc rats largely drives changes in cerebrovascular function.NEW & NOTEWORTHY We demonstrate that the modulation of p66Shc signaling impairs cerebral artery myogenic tone in a low renin model of hypertension. This impairment is dependent upon the genetic background, as modulated p66Shc signaling in Sprague-Dawley rats does not impair cerebral artery myogenic tone.

Author List

Hughes WE, Hockenberry J, Miller B, Sorokin A, Beyer AM

Authors

Andreas M. Beyer PhD Associate Professor in the Medicine department at Medical College of Wisconsin
William E. Hughes Postdoctoral Fellow in the Medicine department at Medical College of Wisconsin
Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Cerebrovascular Circulation
Disease Models, Animal
Female
Homeostasis
Hypertension
Male
Middle Cerebral Artery
NG-Nitroarginine Methyl Ester
Nitric Oxide
Rats
Rats, Inbred Dahl
Rats, Sprague-Dawley
Rats, Transgenic
Renin
Sodium Chloride, Dietary
Src Homology 2 Domain-Containing, Transforming Protein 1