LAUSR

Significance Cerebral small vessel diseases (cSVDs) are a group of related idiopathic and familial pathologies that cause stroke, intracerebral hemorrhage (ICH), and cognitive decline. The underlying mechanisms are poorly understood, and no effective treatment options exist. Here, we investigated a mouse that models a form of cSVD caused by a mutation in the gene encoding type collagen IV alpha1 (COL4A1) to better understand the pathogenesis of the disease. We found that impairment of transient receptor potential melastatin 4 (TRPM4) cation channels disrupted the ability of cerebral arteries from middle-aged mutant animals to constrict in response to physiological levels of intraluminal pressure. Vascular function was restored by acute inhibition of phosphoinositide 3-kinase and transforming growth factor-βreceptors, potentially identifying new therapeutic targets.