The Role of NADPH Oxidase in Regulating Cerebral Vascular Myogenic Tone

Abstract

The myogenic response refers to the intrinsic ability of arteries to constrict to elevated pressure. The underlying mechanism has yet to be elucidated but recent evidence suggests that the angiotensin II type 1 receptor (AT1R) is a key mechanosensor, linking intravascular pressure to tone development. One intriguing aspect of this receptor is its ability to activate NADPH oxidase (Nox), an enzyme responsible for the production of reactive oxygen species. The goal of this study was to ascertain the role of Nox in myogenic tone development. Briefly, rat cerebral arteries were mounted in a myograph, pressurized to 60mmHg and diameter monitored prior to and following the application of apocynin (a general Nox inhibitor) or ML171 (a Nox1 specific inhibitor). Myogenic constriction progressively rose as vessels were pressurized from 20 to 60 mmHg. These pressure‐induced responses were attenuated by apocynin in a concentration dependent manner (37% vs 24% at 60 mmHg) irrespective of whether the endothelium was present or absent. ML171 (30μM) was equally effective at moderating the myogenic response (36% vs 24%); control experiments showed no discernible role for Nox2. Similar attenuating effects were observed in human cerebral arteries. These findings indicate Nox1 is expressed in rat cerebral arterial smooth muscle and may be a regulator of pressure‐induced responses. While the precise downstream mechanism has yet to be resolved, the L‐type Ca2+ channel is a likely target of Nox regulation. This work sheds new light on mechanosensation and how unique signaling proteins impact the ability of resistance arteries to respond to intravascular pressure.Support or Funding InformationThis work is supported by an operating grant from the Natural Sciences and Engineering Research Council of Canada (NSERC) for DG Welsh. DG Welsh is a Rorabeck chair in molecular neuroscience and vascular biology at the University of Western Ontario. AM Hashad is a Vanier scholar (CIHR) and was supported by a salary studentship from Alberta Innovates Health solutions (AIHS).