Basic Research
Description of Scope
The focus of our research program is endothelial biology. Ours is a unique research program from "molecule to man" which spans cell and molecular biological studies, as well as preclinical and clinical investigations focused on the role of the NO Synthase pathway in atherogenesis and angiogenesis. We were the first to demonstrate the anti-atherogenic effects of endothelium-derived Nitric Oxide (EDNO) in animal models. Subsequently we found that EDNO exerts its effects in part by suppressing oxidant-sensitive transcriptional pathways regulating gene expression of molecules involved in monocyte-endothelial cell interaction (e.g., VCAM-1, MCP-1). Most recently, we have focused on asymmetric dimethylarginine (ADMA) as an endogenous inhibitor of the NOS pathway, and the alterations in ADMA metabolism that occur in atherosclerosis and with risk factors for atherosclerosis.
Another area of interest is in the role of the NOS pathway in angiogenesis. We have investigated the role of ADMA as an endogenous antagonist of angiogenesis. Most recently, we have discovered a novel angiogenic pathway mediated by cholinergic receptors of the nicotinic type ( Heeschen C, et al Nat Med 2001 Jul; 7(7):833-9). This has led to a series of productive investigations in the lab to characterize the cellular and genetic determinants of this pathway.
This work has been enriched by a network of collaborations with other Stanford faculty. Our work is well funded by the National Institutes of Health, the American Heart Association, and other non-profit organizations as well as industry.
ADMA: An endogenous inhibitor of NO synthase
Asymmetric dimethylarginine is a competitive inhibitor of NO synthase. In pre-clinical and clinical studies, we have found it to be elevated by hypercholesterolemia, hyperglycemia, hypertriglyceridemia, or hyperhomocysteinemia. In cell culture, we are studying the mechanisms by which ADMA becomes elevated. Reduced metabolism of ADMA by DDAH (dimethylarginine dimethylaminohydrolase) appears to be involved.
Role of NO in Angiogenesis.
In animal models of ischemia or inflammation, we find that vascular NO is required for angiogenesis. ADMA appears to be an endogenous anti-angiogenic agent. Restoration of vascular NO production restores angiogenesis in hypercholesterolemic animals.
Role of NO in atherosclerosis.
We and others have provided evidence that endothelium-derived NO is an endogenous antiatherogenic molecule. NO inhibits monocyte adherence, platelet aggregation and vascular smooth muscle proliferation, key processes in atherosclerosis. Suppression of vascular NO production initiates and sustains atherogenesis. By enhancing vascular NO production (by administration of the precursor L-arginine, or by NO synthase gene therapy), atherogenesis can be inhibited and even reversed in animal models.
Nicotine is an Agent of Angiogenesis
We have made the startling observation that nicotine has potent angiogenic properties. Its angiogenic effects are mediated in part by an endothelial nicotinergic receptor.
The angiogenic effects of nicotine may contribute to tobacco-related diseases (i.e. Judah Folkman and colleagues have demonstrated that growth of atherosclerotic plaque requires neovascularization; tumor angiogenesis is also enhanced in our studies). The mechanisms by which nicotine stimulates angiogenesis are under study in the lab, using cell biological and DNA microarray technology.
ADMA and the NOS pathway
Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger M, Wang B, Tsao PS, Kimoto M, Vallance P, Patterson AJ, Cooke JP: DDAH Regulates NO Synthesis: Genetic and physiological evidence. Circulation 2003; 108: 1043-1048
Weis M, Kledal TN, Lin KY, Panchal SN, Gao SZ, Valantine HA, Mocarski ES, Cooke JP: Cytomegalovirus infection impairs the NOS pathway. Role of ADMA in transplant arteriosclerosis. Circulation 2004 Feb 3;109(4):500-5.
Nicotine and the endothelial nAChR
Zhu B, Heeschen C, Sievers RE, Karliner JS, Parmley WW, Glantz SA and Cooke JP: Second Hand Smoke Stimulates Tumor Angiogenesis and Growth, Cancer Cell 2003; 4(3):191-6
Heeschen C, Jang J, Hoai-Ky V, Kaji S, Yang P, Hu RS, Cooke JP: Nicotine is an agent of angiogenesis. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med 2001 Jul; 7(7):833-9