Regulation of Blood Flow in Humans

Dr. Mark Creager's laboratory studies the role of the endothelium, and its biologically active substances such as nitric oxide, on the regulation of blood flow in patients with atherosclerosis and its risk factors. By using a variety of techniques to examine blood flow in humans, including arterial cannulation, venous occlusion strain gauge plethysmography, and vascular ultrasonography, we found that endothelium-dependent relaxation was impaired in patients with atherosclerotic risk factors, including hypercholesterolemia, diabetes mellitus, and hypertension, when compared to responses observed in matched healthy subjects. Much of the laboratory’s efforts to elucidate mechanisms of endothelial dysfunction have concentrated on the role of intracellular signaling pathways and oxidant stress. Superoxide anion inactivates nitric oxide to peroxynitrite, and many of the atherosclerosis risk factors are associated with increased production of oxygen-derived free radicals. We determined that antioxidant vitamins improve endothelium-dependent vasodilation in patients with either type I or type II diabetes mellitus, enabling us to conclude that oxidant stress reduces the availability of nitric oxide. Ongoing studies are evaluating the relationship between insulin resistance and vascular function. The small GTP binding protein Rho, and its downstream effector, Rho kinase, have been implicated in many of the pathologic processes that underlie atherosclerosis. Activation of the Rho/Rho kinase pathway reduces the bioavailability of nitric oxide in experimental models of vascular injury. We found that inhibition of the Rho kinase pathway improved endothelial function in patients with coronary artery disease and hypercholesterolemia. In addition, the laboratory is evaluating mechanisms that affect blood flow regulation and clinical outcomes in patients with peripheral artery disease. We are also conducting clinical trials for novel pharmacotherapies in patients with peripheral artery disease and intermittent claudication.

References:

Nohria A, Grunert ME, Rikitake Y, Noma K, Prsic A, Ganz P, Liao JK, Creager MA. Rho kinase inhibition improves endothelial function in human subjects with coronary artery disease. Circ Res 2006;99:1426-1432.

Goldfine AG, Beckman JA, Betensky RA, Devlin H, Hurley S, Varo N, Schonbeck U, Patti ME, Creager MA. Family history of diabetes is a major determinant of endothelial function. J Am Coll Cardiol 2006;47:2456-2461.

Beckman JA, Goldfine A, Dunaif A, Gerhard-Herman M, Creager MA. Endothelial function varies according to insulin resistance type. Diabetes Care 2007;30:1226-1232.

Perlstein TS, Pande RL, Beckman, JA, Creager MA. Serum total bilirubin level and prevalent lower extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 . Arterioscler Thromb Vasc Biol. 2008;28:166-172.