The role of autophagy in vascular homeostasis and vascular reactivity is poorly understood. In this proposal, we characterize mice lacking autophagic flux in the endothelial or smooth muscle cell layer. Remarkably, inhibiting autophagic flux in vascular smooth muscle cells appears to recapitulate aspects of the rare human disease Hutchinson-Gilford Progeria Syndrome (HGPS). This segmental progeriod condition is caused by a dominant mutation in the lamin A/C gene. While HGPS is an accelerated aging syndrome, most of the fatalities result from vascular complications (e.g. myocardial infarction and stroke). Analysis of human subjects, as well as characterization of mouse models of the disease, demonstrate profound changes in the large arteries. These changes are believed to be secondary to the vascular accumulation of progerin, an altered form of lamin A whose production is favored in patients with HGPS. Interestingly, progerin can also accumulate in the blood vessels of normal individuals as a function of aging. As such, these observations suggest that the lessons learned from this rare progeriod syndrome, HGPS, may have wider applications. In this proposal, we explore the role of autophagy in the segmental vascular pathology of HGPS. Using a variety of novel mouse models where autophagy has been conditionally deleted in the vessel wall, as well as human induced pluripotent stem cells (iPSCs) in which specific genes have been deleted via CRISPR- based strategies, we propose to study the mechanistic connection between impaired autophagy, HGPS pathology and normal vascular aging. As such, these studies provide the first characterization as to how endothelial and vascular smooth muscle cell autophagy regulates vascular homeostasis.
A decline in autophagy might regulate vascular aging. In that regard, Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating genetic condition characterized by segmental aging of the vasculature. This proposal seeks to understand the molecular basis of HGPS and the role of autophagic flux in normal vascular aging.