Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation.

Area of Science:

• Neuroscience
• Cardiovascular Science
• Pharmacology

Background:

• Endothelin-1 (ET1) is a vasoconstrictor linked to cerebrovascular events like stroke.
• ET1 levels rise in stroke, subarachnoid hemorrhage, brain trauma, and associated risk factors.
• Previous research focused on ET1's smooth muscle effects, with limited understanding of its role in cerebrovascular regulation.

Purpose of the Study:

• To investigate how ET1 disrupts critical mechanisms regulating cerebral blood flow.
• To test the hypothesis that ET1 increases cerebrovascular risk by impairing cerebral blood flow regulation.

Main Methods:

• Male C57Bl6/J mice with cranial windows received intravenous vehicle or ET1 infusions.
• Cerebral blood flow in the somatosensory cortex was measured using laser Doppler flowmetry.
• In vitro studies assessed endothelial nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation.

Main Results:

• ET1 infusion elevated mean arterial pressure and blunted activity- or acetylcholine-induced increases in cortical blood flow.
• These effects were blocked by the ET(A) receptor antagonist BQ123 and dependent on Rho-associated protein kinase (ROCK) activity.
• ET1 suppressed endothelial NO production, linked to ROCK-dependent eNOS phosphorylation.

Conclusions:

• Increased ET1 levels impair cerebral blood flow regulation by modulating eNOS phosphorylation and NO production via ROCK.
• This ET1-induced cerebrovascular dysfunction may elevate cerebrovascular risk by reducing reserves and increasing ischemic vulnerability.