Our laboratory is interested in the molecular genetics of vascular diseases. We utilize several approaches, including molecular and cellular biology studies, genetic studies in mice, and clinical investigations in patients with vascular diseases. Our focus is on the genetics and genomics of vascular remodeling during common, complex cardiovascular diseases and during premature aging syndromes. Vascular proliferative diseases are characterized by smooth muscle cell (VSMC) proliferation and migration. We have completed our studies of Cyclin-dependent kinase inhibitors, p21(Cip1) and p27(Kip1), which are upregulated during vascular cell proliferation and negatively regulate growth of vascular cells. We hypothesized that absence of either p21(Cip1) or p27(Kip1) in apolipoprotein E (apoE)-deficiency may increase atherosclerotic plaque formation. Compared to apoE(-/-) aortae, both apoE(-/-)/p21(-/-) and apoE(-/-)/p27(-/-) aortae exhibited significantly more atherosclerotic plaque following a high-cholesterol regimen. This increase was particularly observed in the abdominal aortic regions. Deficiency of p27(Kip1) accelerated plaque formation significantly more than p21(-/-) in apoE(-/-) mice. This increased plaque formation was in parallel with increased intima/media area ratios. Deficiency of p21(Cip1) and p27(Kip1) accelerates atherogenesis in apoE(-/-) mice. These findings have significant implications for our understanding of the molecular basis of atherosclerosis associated with excessive proliferation of vascular cells. We also completed a study on role of STAT3 arginine methylation by PRMT2 in the regulation of leptin signaling and energy homeostasis. We identified that PRMT2-/- mice are hypophagic, lean, and have significantly reduced serum leptin levels. This lean phenotype is accompanied by resistance to food-dependent obesity and an increased sensitivity to exogenous leptin administration. PRMT2 co-localizes with STAT3 in hypothalamic nuclei, where it binds and methylates STAT3 through its Ado-Met binding domain. Absence of PRMT2 results in decreased methylation and prolonged tyrosine phosphorylation of hypothalamic STAT3, which was associated with increased expression of hypothalamic pro-opiomelanocortin following leptin stimulation. These data elucidate a molecular pathway that directly links arginine methylation of STAT3 by PRMT2 to the regulation of leptin signaling, suggesting a potential role for PRMT2 antagonism in the treatment of obesity and obesity-related syndromes. We investigated the genomics of coronary restenosis, which is the recurrence of a coronary artery occlusion following stent placement due to VSMC proliferation. The genetic analyses included mRNA expression profiling, genome-wide association study, linkage analysis, and integrative analyses. The goal is to identify genomic profiles of patients with recurrent restenosis, so as to advance our understanding of VSMC driven remodeling diseases and to target potential molecular therapies. Finally, a major area of investigation is the Hutchinson-Gilford progeria syndrome (HGPS), caused by the production of progerin, a mutant form of the nuclear architectural protein lamin A. The syndrome is characterized by premature aging, most notably cardiovascular disease that eventually leads to death from myocardial infarction or stroke, usually in their second decade of life. In collaboration with Dr. Leslie Gordon (Brown University, Providence, RI), we have undertaken a comparative evaluation of histological overlap between HGPS and the cardiovascular disease of aging. We analyzed the cardiovascular tissues from two genetically-confirmed cases of HGPS, a 9-year-old girl and a 14-year-old boy, who both died of myocardial infarction. Both children had severe coronary artery and aortic atherosclerosis with a number of features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels in all organs examined. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. HGPS patients had high levels of nuclear progerin in all tissues analyzed, including vascular smooth muscle cells and adventitial fibroblasts. Importantly, older non-HGPS individuals also exhibited progerin-positive cells in major vessels, with progerin increasing with donor age.