Mechanisms of Vascular Damage: Cell Death Across Cardiovascular Toxicity and Aging

Abstract

How endothelial injury is translated into organ dysfunction remains a fundamental unresolved question in vascular biology, particularly in the settings of cancer therapy and aging. This dissertation examines two challenges to vascular integrity that carry major clinical consequences: chemotherapy- and radiation-associated endothelial injury that contributes to cardiovascular risk in cancer survivors, as well as age-related blood–brain barrier (BBB) dysfunction that increases susceptibility to neurocognitive decline and other age-associated disorders. Despite their differences, these contexts converge on a shared vulnerability—endothelial susceptibility to apoptosis—and its downstream consequences for vascular dysfunction and disease. This work is guided by a unifying framework: baseline apoptotic priming, governed in part by BCL-2 family regulation, sets the threshold for mitochondrial commitment to cell death and thereby shapes how endothelial cells respond to stress. In peripheral tissues, I show that vascular cells across multiple organs exhibit features consistent with heightened apoptotic priming across the ages examined, providing a mechanistic basis for sensitivity to cytotoxic cancer therapies and a framework for understanding how normal-tissue vascular injury may contribute to late cardiovascular complications. To connect experimental findings to patient-relevant signals, I leverage the global pharmacovigilance database VigiBase to evaluate clinical associations consistent with therapy-associated vascular toxicities. In the aging brain, I investigate how age reshapes endothelial state and alters BBB vulnerability to damage. Using a protocol developed to isolate and purify CD31⁺ brain endothelial cells from young (3-month-old) and aged (23-month-old) mice, I find that aging is associated with increased baseline inflammatory gene expression and modest upregulation of apoptosis-related signaling, and that these features are exacerbated after ionizing radiation. Complementary in vivo studies show greater endothelial cell death in aged mice following γ-radiation, along with delayed clearance of dead cells compared with young adults, suggesting that age-dependent tissue context influences both the magnitude and temporal dynamics of neurovascular injury. Together, these studies provide an integrated view of how apoptosis and related stress-response programs shape vascular health across tissues, life stages, and injury contexts. By linking cancer therapy–associated vascular injury and age-associated BBB dysfunction through the lens of cell death vulnerability, this work positions apoptotic priming as a unifying, yet context-dependent, guideline for understanding endothelial dysfunction and motivates strategies to preserve vascular integrity across disease-relevant stresses.