Vascular Proliferative Resilience - SUMMARY In adults, the generation of new blood vessels is confined to capillaries, where it facilitates tissue growth, remodeling and repair. De novo expansion of the microvascular network occurs through active proliferation and migration of endothelial cells. In contrast, endothelial proliferation in adult large blood vessels, such as arteries, is thought to be rare, except for responses to trauma. We have shown that endothelial injury following physical trauma to the aorta triggers a rapid proliferative response leading to the prompt repair of the inner vascular lining, known as the endothelium. Our preliminary findings indicate that, in addition to physical trauma, chronic inflammation can lead to the demise of endothelial cells in large vessels. We further found that endothelial cell death was associated with a concurrent induction of proliferation, providing a balance between cell loss and renewal that ensures continuity of the endothelial barrier. However, this proliferative response is impaired in aging, creating a deficit in endothelial coverage that results in the deposition of fibrin. These results suggest a previously unrecognized deterioration in the ability of large vessels to maintain adequate regulation of vascular integrity and reveal an unmet need in cardiovascular biology. To this end, we propose experiments to decipher the dynamics, spatial context, and molecular regulators of proliferation in the endothelial lining of the aorta. We used a novel mouse model that precisely titers arterial endothelial cell death. Using this model, we found that proliferation quickly compensates for the lost cells and highlights the important role of endothelial cell proliferation to restore such deficits. The findings also uncovered a remarkable proliferative capacity in the aorta that was previously unrecognized. Importantly, pharmacological blockade of this proliferative activity resulted in organismal death. The findings support the novel concept that ongoing proliferative repair of large vessel endothelial cells is an essential and previously unsuspected biological function. These data prompted several questions: What is the proliferative capacity of aortic endothelial cells? What stressors mediate cell death in the aortic endothelium? Is the reserve proliferative capacity of the endothelium impacted by metabolic alterations associated with common comorbidities (hyperlipidemia, diabetes) or oxygen-reperfusion events? Energized by these questions and our robust preliminary data, we hypothesize that Endothelial cells of the aorta retain a significant proliferative reserve that is continuously available for repair. This capacity is restrained by metabolic comorbidities that limit vascular resilience and cell-cycle entry. Two aims were developed to test this hypothesis: (1) To characterize the proliferative reserve of endothelial cells in the aorta. and (2) To determine whether metabolic comorbidities impact aortic endothelial proliferative resilience. These broadly defined aims have been conceptualized to fill gaps in our knowledge of fundamental processes in endothelial cell biology and to exploit this information for mechanistic studies and medical applications.
