Sildenafil promotes ischemia-induced angiogenesis through a PKG-dependent pathway.
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.


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.
Senthilkumar
Annamalai
A
LSU Health Sciences Center-Shreveport, Department of Cardiology , 1501 Kings Hwy, Shreveport, LA 71130, USA.
Smith
Ray D
RD
Khitha
Jayant
J
Arora
Neeraj
N
Veerareddy
Srikar
S
Langston
Will
W
Chidlow
John H
JH
Barlow
Shayne C
SC
Teng
Xinjun
X
Patel
Rakesh P
RP
Lefer
David J
DJ
Kevil
Christopher G
CG
D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D016491:Peripheral Vascular Diseases / Q000188:drug therapy; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases