Col4a1 mutation in mice causes defects in vascular function and low blood pressure associated with reduced red blood cell volume

Collagen type IV is the major structural component of the basement membrane and COL4A1 mutations cause adult small vessel disease, familial porencephaly and hereditary angiopathy with nephropathy aneurysm and cramps (HANAC) syndrome. Here, we show that animals with a Col4a1 missense mutation (Col4a1(+/Raw)) display focal detachment of the endothelium from the media and age-dependent defects in vascular function including a reduced response to nor-epinephrine. Age-dependent hypersensitivity to acetylcholine is abolished by inhibition of nitric oxide synthase (NOS) activity, indicating that Col4a1 mutations affect vasorelaxation mediated by endothelium-derived nitric oxide (NO). These defects are associated with a reduction in basal NOS activity and the development of heightened NO sensitivity of the smooth muscle. The vascular function defects are physiologically relevant as…