PROJECT SUMMARY / ABSTRACT Arterial dysfunction is a causal factor in the leading causes of death in the United States. Sex differences in the presentation, resiliency and risk profile of arterial pathologies are well established, yet knowledge to clarify the molecular determinants of these differences remain sparse. Aortic aneurysms and dissections exhibit clear and consistent sex differences in their presentation and treatment outcomes. Women are diagnosed significantly less frequently and at later ages than males, even in cases of hereditary aneurysm such as Marfan Syndrome (MFS) where causal mutations are inherited with equal frequency between males and females. When diagnosed, however, women exhibit poorer outcomes and prognosis relative to men for reasons likely attributable to both biological and socially driven factors. The biological underpinnings driving resiliency against aortic aneurysms and dissections in women remain unclear, but their definition will 1) identify protective pathways in females that could be leveraged to improve disease prevention and management in males and 2) understand the drivers of reduced resiliency in the females who do exhibit severe disease. In this proposal, we leverage a well-established mouse model of MFS, gonadectomy and hormone replacement, and cutting-edge proteomics in order to examine how the female sex hormones estrogen (E2) and progesterone (P4) intersect with chromosomally defined sex to affect well established AoR aneurysm phenotype (Aim 1). We will then combine in vitro experiments in human iPSC-models of normal and MFS vascular cells with in vivo validation in mice in order to test two specific hypotheses regarding how E2 and P4 affect known pathways involved in aneurysm pathogenesis; Angiotensin II (Ang II) signaling (Aim 2) and mechano/matrixsensing imbalance driven by specific integrin heterodimers (Aim 3). Interestingly, while severe of aortic root (AoR) aneurysm and dissection appear biased toward males, non- atherosclerotic Spontaneous Coronary Artery Dissection (SCAD) is clearly biased toward females and is a leading cause of acute coronary syndromes in young women. Among its risk factors are pregnancy and existing hereditary arteriopathies, such as Marfan Syndrome (MFS). Interestingly, Fibrillin-1 (Fbn1), the gene that causes MFS, has been identified as a candidate gene among patients with SCAD in recent genome wide association studies. Key molecular differences between the aortic and coronary arteries may confer critical molecular variance in response to hormones that results in disparate risk and resiliency due to sex. As an additional exploratory arm in each of the above Aims, we will investigate whether coronary artery pathology demonstrate ‘mirror image’ risk or resiliency signatures between hormone-altered male and female MFS mice in an effort to provide some of the first fundamental models for the study of the female-biased condition of SCAD. The insights gained from our studies ...