Project summary Fibromuscular dysplasia (FMD) is a non-atherosclerotic, systemic arteriopathy with excess burden on women. FMD may have varying manifestations, including hypertension, stroke and myocardial infarction, among others, depending on the arterial beds involved by arterial stenosis, aneurysm, dissection or tortuosity. Arterial dissections are recognized as a major manifestation and cause of substantial morbidity and mortality risk. Genetic susceptibility loci for FMD and arterial dissections identified thus far implicate arterial smooth muscle and its corresponding extracellular matrix. The genetic architecture of these arterial diseases is emerging as variable, with contributions of a complex genetic architecture, rare heritable variants in a subset of cases, and potential modifier genes. The proposed studies will build upon the R35 awarded to Dr. Ganesh to support the training of postdoctoral fellow Cameron Pinnock, PhD and evaluate the genetic and allelic spectrum of spontaneous coronary artery dissection (SCAD) and FMD in novel bioengineered cellular and tissue models. These studies are within scope and fully aligned with the goal of the R35 award as originally stated to precisely define the genetic basis of arterial fibrodysplasia and employ relevant model systems for gene and variant mechanistic testing, resolution of genetic variants of uncertain significance, testing influences of potential modifier genes, and analysis of gene regulatory mechanisms, particularly those relevant to vascular sex differences and female-biased cardiovascular disease. We will test the hypothesis that the genetic influences on FMD and SCAD alter the vascular smooth muscle matricellular unit in manners that render the artery susceptible to loss of tissue integrity. The expected outcome of the proposed studies will be the successful integration of genomics and functional studies with new engineered models that provide new insights into the mechanisms of arterial dysplasia.