on June 21, 2007
Published online before print June 21, 2007, doi: 10.1161/ATVBAHA.107.147421
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Submitted on February 16, 2007
Accepted on June 1, 2007
Sildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway
Annamalai Senthilkumar ;
From the Departments of Cardiology (A.S., R.D.S., J.K., N.A., S.V.), Pathology (W.L., C.G.K.), and Molecular and Cellular Physiology (W.L., J.H.C., S.C.B., C.G.K.), Louisiana State University Health Sciences Center, Shreveport; the Department of Molecular and Cellular Pathology and Center for Free Radical Biology (X.T., R.P.P.), University of Alabama at Birmingham; and the Department of Medicine, Division of Cardiology (D.J.L.), Albert Einstein College of Medicine, New York.
* To whom correspondence should be addressed. E-mail: ckevil{at}lsuhsc.edu.
Background--Peripheral artery disease (PAD) is a prevalent cardiovascular disorder that results in tissue ischemia which can progress to critical limb ischemia. Restoration of tissue perfusion in the setting of chronic ischemia through stimulation of arteriogenesis and angiogenesis remains a key therapeutic target for PAD. However, experimental therapeutics, including growth factor and gene therapy, have had little clinical success indicating the need for a better understanding of molecular pathways required for therapeutic angiogenesis.
Methods and Results--Here we report that phosphodiesterase-5 inhibition by sildenafil significantly increases vascular perfusion, tissue blood flow, and vascular density during chronic ischemia of the mouse hind limb. Importantly, sildenafil therapy did not alter any of these parameters in nonischemic limbs. Sildenafil increased tissue cGMP levels independently of increases in nitric oxide production, and sildenafil therapy stimulated angiogenesis in ischemic limbs of eNOS-/- and iNOS-/- mice. Lastly, sildenafil-mediated angiogenic activity was blocked by inhibition of protein kinase G using the PKG antagonist DT-3.
Conclusions--These data demonstrate that sildenafil therapy results in increased angiogenic activity through a PKG-dependent pathway that is independent of nitric oxide production or NOS activity and identify the angiogenic therapeutic potential of sildenafil for critical limb ischemia.
Key words: ischemia • angiogenesis • nitric oxide • PKG • sildenafil • PDE-5 inhibition
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