Changes in the Vascular Extracellular Matrix as a Potential Cause of Myocyte Loss via Anoikis in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Abstract

Objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a generalized vasculopathy caused by mutations in the NOTCH3 gene, leading to degeneration and loss of vascular smooth muscle cells (VSMC). The relationship between NOTCH 3 mutations and VSMC death is unknown. One possible cause of myocyte deficit may be anoikis, a special type of apoptosis due to loss or inappropriate cell adhesion to extracellular matrix. Method: To verify this hypothesis we examined immune expression of main compounds of vascular extracellular matrix (laminin, fibronectin and collagen IV) and selected metallo proteinases (MMP-2, MMP-3, and MMP-9) in cerebral, skin and skeletal muscle arterial vessels in autopsy material and biopsy specimens of CADASIL patients. Results: The immmune reactions revealed decreased expression of laminin and increased expression of collagen IV and fibronectin in arterial vessels. Moderately intense immune reactivity to MMP-9 and MMP-2 was present while immune reactivity to MMP-3 was absent. Conclusion: Quantitative and qualitative changes in vascular extracellular matrix found in CADASIL vessels may lead to VSMC loss via anoikis pathway.