The Nuclear-Cytoskeletal Interface Is a Vulnerability in Aging Endothelium

Abstract

Vascular aging is a fundamental driver of age-related cardiovascular diseases. Endothelial cells (ECs) lining the vascular lumen of capillaries are specialized, thin cells that supply tissues with metabolites, and their loss in aging poses a threat to tissue perfusion and ischemia risk. Mechanisms causing capillary dropout in aging are largely unknown, although VEGF signaling deficiency is implicated. To identify mechanisms involved in vascular aging, we investigated mice with the accelerated aging disorder Progeria, and aged wildtype mice. At the organismal level, Progerin expression reduced sprouting angiogenesis and capillary density in neonatal mouse retinas, which impaired tissue perfusion and increased DNA damage compared to wildtype littermates. Progeric capillaries and aortic ECs displayed a disrupted nuclear-cytoskeletal interface that was shared with aged wildtype mice. 4D EC sprouts derived from Progeria mice had mispositioned nuclei at sprouting tips and bulging nuclei that failed to flatten and obstructed lumen formation, demonstrating cell autonomous defects. Progerin expression in human ECs likewise affected nuclear positioning and flattening and prevented sprouting and lumen formation. Mechanistically, Progerin expression altered LINC complex protein abundance resulting in a failed connection with cytoskeletal Actin and the intermediate filament protein Vimentin. Impairment of the nuclear-cytoskeletal interface was conserved in Progeria patient derived ECs, and partially rescued by inhibiting Progerin with the drug, Progerinin. Taken together, our results reveal that nuclear positioning and flattening is required for angiogenic sprouting and lumen formation respectively and identify the nuclear-cytoskeletal interface as a vulnerability for age-related microvascular dropout and a target for therapeutic intervention.