Studies Find Possible Drug Targets For Improving Vascular Health

In a related study this month in the Journal of ClinicalInvestigation, the same investigator, William Sessa, professor ofpharmacology 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 enhancingnew blood vessel growth following a blockage due to ischemia.

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

Sessa said the study in PNAS implies that therapeuticapproaches to improve blood flow and arteriogenesis in patients withperipheral vascular disease by using a single cytokine will havelimited utility unless impairments in the enzyme nitric oxide functionare taken into account and corrected.

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

PNAS 102: 10999-11004
The Journal of Clinical Investigation 115: 2119-2127