Endothelial Cell Bulge Occludes the Vasa Vasorum in the Cerebellar Vascular Hyalinosis Lesions

Background The remodeling of the cerebral vascular wall contributes to the occurrence of ischemic stroke in systemic hypertension patients, representing a leading cause of death in the U.S. and worldwide. Cerebral vascular remodeling in systemic hypertension is characterized by progressive degradation of structural components of each layer of the vessel wall with the subsequent transformation to hyaline material leading to the thickening vascular wall and lumen narrowing. The vasa vasorum as a network of small blood vessels supplying the blood to the vascular wall tissues contributes to the damage vascular structure and results in the formation of hyalinosis. The occlusion of vasa vasorum contributes to development of cerebral vascular hyalinization in systemic hypertension. However, mechanisms of occlusion of vasa vasorum that contribute to the brain vascular remodeling events have not been well defined. Lack of such knowledge interferes with the development of therapeutic strategies to reduce the occurrence of ischemic stroke. Methods & Results Light microscopy and transmission electron microscopy (TEM) of hyalinized cerebral vessels from human patients who suffered from systemic hypertension and died by ischemic stroke visualized the occlusion of the vasa vasorum due to the formation of the “bulge” structure that protrude from the endothelial cells. Treatment of microvascular endothelial cell with adrenaline (a major biogenic amine that are increased in the blood due to disbalance of neurohumoral homeostasis in systemic hypertension) resulted in a cytoskeletal rearrangement that contributes to the formation of the bulge‐like structure in the vasa vasorum of the brain vessels with hyalinosis lesion. The adrenaline activated clathrin‐mediated endocytosis of endothelial cells that in turn elicited SNX9/N‐WASP‐dependent disruption of cytoskeleton. siRNA knockdown of SNX9 inhibited endocytosis and prevented the adrenaline‐induced bulge formation in human microvascular endothelial cells. TEM visualized the adrenaline‐induced an increase endocytosis of the endothelial cells. Immunofluorescence staining showed the actin filament structural reorganization and TEM confirmed myofilament damage within endothelial cells. Adrenaline treatment induced post‐translational modifications of N‐WASp as a regulator of actin polymerization. Conclusions This is the first demonstration that adrenaline contributes to the occlusion of vasa vasorum in the hyalinized cerebral vascular wall that will allow to the development new strategies that can be used to prevent ischemic stroke. Support or Funding Information Supported by NIH