Studies Find Possible Drug Targets For Improving Vascular Health

In a related study this month in the Journal of Clinical Investigation, the same investigator, William Sessa, professor of pharmacology at Yale School of Medicine, found that the protein kinase, Akt1, one of three Akt molecules involved in growth, survival, metabolism and other cellular functions, is responsible for enhancing new blood vessel growth following a blockage due to ischemia.

In the PNAS study Sessa used mice missing the endothelial nitric oxide synthase gene and found they had impaired ability to build arteries and capillaries, which are important for providing blood flow to muscle upon exercise training. Sessa and his colleagues also succeeded in using gene therapy to reverse the effects of the missing gene, which rescued limbs in danger of dying because of ischemia. Ischemia is a severe reduction of blood flow and nutrients, usually because of a blood clot or atherosclerosis.

Sessa said the study in PNAS implies that therapeutic approaches to improve blood flow and arteriogenesis in patients with peripheral vascular disease by using a single cytokine will have limited utility unless impairments in the enzyme nitric oxide function are taken into account and corrected.

His study on the Akt1 molecule is believed to provide the first direct evidence that changes in capillary formation and vascular leakage induced by the angiogenic factor vascular endothelial growth factor (VEGF) requires Akt1. VEGF is produced by ischemic tissue, as well as tumor cells, to stimulate the formation of new blood vessels. The data also suggest that inhibition of Akt1 signaling may be an effective strategy to block not only tumor growth, but the pathological growth of new blood vessels from existing blood vessels that are mediated by vascular endothelial growth factor. However, Sessa said, this strategy may be a “double-edged sword” since inhibition of Akt may also worsen peripheral vascular disease secondary to atherosclerosis, diabetes or aging. The studies in PNAS and JCI are synergistic since Akt can regulate nitric oxide synthase function by increasing its activity.

Yu J, deMuinck ED, Zhuang Z, Drinane M, Kauser K, Rubanyi GM, Qian HS, Murata T, Escalante B, Sessa WC.
Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve.
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10999-1004.

Ackah E, Yu J, Zoellner S, Iwakiri Y, Skurk C, Shibata R, Ouchi N, Easton RM, Galasso G, Birnbaum MJ, Walsh K, Sessa WC.
Akt1/protein kinase Balpha is critical for ischemic and VEGF-mediated angiogenesis.
J Clin Invest. 2005 Aug 1;115(8):2119-2127.

Message posted by: Frank S. Zollmann