My laboratory studies the biological roles of nitric oxide (NO) in the control of cerebrovascular blood flow, cardiovascular hemodynamics, stroke and atherosclerosis. We have used genetic manipulation of mice to study the roles of neuronal and endothelial nitric oxide synthases (nNOS and eNOS). We are using nNOS and eNOS knockout and transgenic animals to define the roles of NO in regulating cerebral blood flow and response to cerebral ischemia. We are also studying the mechanisms of endothelial dysfunction that lead to atherosclerosis. Endothelial NOS mutant mice develop more neointima in response to vessel injury and diet-induced atherosclerosis, demonstrating that eNOS deficiency alone is sufficient to alter vascular injury responses. We are interested in how metabolic abnormalities in obesity, diabetes, and metabolic syndrome lead to atherosclerosis. To this end, we have generated eNOS transgenic and knockin mice carrying specific mutations that alter eNOS phosphorylation by Akt kinase. Our hope is to define the mechanisms of endothelial dysfunction, and to identify new approaches to modulating these mechanisms. In addition to my laboratory research, I am a practicing cardiologist in the MGH Cardiology Division. I am the founding Director of the MGH Cardiology Metabolic Syndrome Program in the Cardiovascular Disease Prevention Center for the evaluation and management of patients with metabolic syndrome, obesity, and increased cardiac risks.