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 will reveal putative risk and resiliency mechanisms that can be leveraged for prevention
and therapeutic strategies applicable to both sexes.