Sildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway

Abstract

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.

Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis

“…We have recently reported that increasing intracellular cGMP through the inhibition of phosphodiesterase 5 significantly enhances ischemia induced angiogenesis through a phosphoglycerate kinase pathway (31). However, we found that nitrite therapy did not sustain a significant increase in ischemic tissue cGMP levels.…”

“…Hind-limb ischemia was induced in wild-type mice, as we have reported by ligating the left common femoral artery proximal to origin of profunda femoris artery (31).…”

“…Successful reperfusion of ischemic tissues depends on stimulation of angiogenic activity necessary for restoration of tissue blood flow (27,31). Fig.…”

“…These data reveal a delayed effect of nitrite therapy on tissue nitrosothiol, C-/N-nitroso compounds, and ironnitrosyl proteins and demonstrate preferential production of NO containing intermediates in ischemic tissues. NO activates soluble guanylate cyclase, resulting in elevated cGMP levels that can augment ischemia-induced angiogenesis (31). Therefore, we examined whether chronic sodium nitrite therapy involved increased cGMP in augmenting ischemia-induced angiogenesis.…”

Capillaries, Old Age and Alzheimer’s Disease

“…They include sildenafil (Viagra) and tadalafil (Cialis), which are prescribed to treat various medical conditions, including erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension (PAH) [25]. The drugs' intended effect in patients is to produce vasodilation, but in animal studies both have been shown also to induce capillary formation in ischemic tissues/ organs [26][27][28][29][30][31]. These drugs regulate a key intermediate in metabolic pathways leading to capillary formation, as outlined elsewhere [32].…”