Vascular smooth muscle cells (VSMCs) have a dramatic ability to alter their phenotype to adopt different roles in diverse tissues and organs and contribute to vascular physiology, growth, remodeling, and repair. The inappropriate SMC phenotypic modulation, however, results in a number of cardiovascular pathologies, including aortic aneurysm, atherosclerosis, vascular malformation, systemic and pulmonary hypertension. To this date, there has been no cure for these conditions, and surgical repair or transcatheter interventions are often associated with the recurrence of the disease or major complications. PRDM6 is an SMC-specific epigenetic regulator that is most abundant in vascular smooth muscle cells (VSMCs) and regulates its plasticity. Genetic variants in the PRDM6 gene have been associated with a wide range of traits, including blood pressure regulation, reduced thoracic aortic distensibility and aortic dilation, intracranial aneurysm, coronary artery disease, type II diabetes (T2D), BMI, and atrial flutter by genome-wide association studies (GWAS). How PRDM6 is transcriptionally regulated and the epigenetic mechanisms by which it regulates gene transcription are not known. Our goal is to outline the regulatory landscape of PRDM6 in the human thoracic aorta, and identify PRDM6 enhancers that by regulating PRDM6 transcription determine the aortic diameter by combining high throughput reporter assays with genome-wide association data. Further, we will delineate the mechanisms of gene regulation by PRDM6 in mouse aortic SMCs (ASMCs) by genome-wide ChIPseq assays and identify PRDM6-regulated genes in peak GWAS loci for cardiovascular diseases. Finally, we will examine the role of Wnt signaling in aortic dilation and examine the effects of its inhibition in rescuing the trait. These findings are expected to lead to target identification for the development of novel therapeutics for aortic aneurysms and other diseases arising from dysregulated VSMCs, including aortic coarctations, and systemic hypertension.