Sildenafil promotes ischemia-induced angiogenesis through a PKG-dependent pathway
Annamalai Senthilkumar1, Ray D Smith, Jayant Khitha
1LSU Health Sciences Center-Shreveport, Department of Cardiology , 1501 Kings Hwy, Shreveport, LA 71130, USA.
Arteriosclerosis, Thrombosis, and Vascular Biology
|June 23, 2007
Summary
Sildenafil, a phosphodiesterase-5 inhibitor, promotes therapeutic angiogenesis in ischemic limbs by activating a protein kinase G pathway. This treatment enhances vascular density and blood flow without affecting non-ischemic tissues.
Area of Science:
- Cardiovascular Research
- Vascular Biology
- Pharmacology
Background:
- Peripheral artery disease (PAD) causes tissue ischemia, potentially leading to critical limb ischemia.
- Restoring perfusion via arteriogenesis and angiogenesis is crucial for PAD treatment.
- Current experimental therapies for PAD have limited clinical success, highlighting the need for novel approaches.
Purpose of the Study:
- To investigate the therapeutic potential of sildenafil in promoting angiogenesis in ischemic limbs.
- To elucidate the molecular pathways involved in sildenafil-mediated angiogenesis.
Main Methods:
- Sildenafil treatment in a mouse hind limb ischemia model.
- Assessment of vascular perfusion, blood flow, and vascular density.
- Measurement of tissue cyclic guanosine monophosphate (cGMP) levels.
- Evaluation of angiogenesis in endothelial nitric oxide synthase knockout mice.
- Inhibition of protein kinase G (PKG) to assess pathway involvement.
Main Results:
- Sildenafil significantly increased vascular perfusion, blood flow, and vascular density in ischemic hind limbs.
- No changes were observed in non-ischemic limbs following sildenafil therapy.
- Sildenafil elevated tissue cGMP levels independently of nitric oxide production.
- Angiogenesis was stimulated by sildenafil even in the absence of eNOS or iNOS activity.
- Inhibition of PKG abolished the angiogenic effects of sildenafil.
Conclusions:
- Sildenafil therapy promotes angiogenesis through a PKG-dependent pathway.
- This mechanism is independent of nitric oxide production or NOS activity.
- Sildenafil demonstrates significant therapeutic potential for treating critical limb ischemia.
Related Concept Videos
01:28Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors
Phosphodiesterase 5 (PDE5) inhibitors are potent enzymes that function to hydrolyze cyclic nucleotides to their corresponding 5' monophosphates. Their unique biochemical properties have been applied in treating Pulmonary Arterial Hypertension (PAH).
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...
01:28Nitric Oxide Signaling Pathway
Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure to...
01:24Regulation of Angiogenesis and Blood Supply
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
01:10Mechanism of Angiogenesis
Blood vessel formation starts early during embryonic development, around day 7. In the extraembryonic yolk sac, mesodermal precursor cells called hemangioblast proliferate and differentiate into angioblast. Angioblasts express vascular endothelial growth factor receptor 2 or VEGFR2, which binds VEGF-A, a proangiogenic factor, guiding blood vessel formation. VEGF signaling promotes angioblasts to form a blood island in the developing embryo. Angioblasts further differentiate, giving rise to...
01:23Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists
Prostacyclin receptor agonists are a class of therapeutic agents integral to managing pulmonary arterial hypertension (PAH). These drugs operate by mimicking the action of prostaglandin I2, or PGI2, a naturally occurring compound in the body.
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
01:23Antihypertensive Drugs: Vasodilators
Vasodilators, primarily affecting the smooth muscles within arterial and venous walls, are commonly used for hypertension treatment. Medications such as minoxidil and hydralazine primarily target arteries and arterioles, while sodium nitroprusside acts on arterioles and venules. Minoxidil, functioning as a prodrug, is metabolized by hepatic sulfotransferase into its active form, minoxidil sulfate, after oral administration. This metabolite binds to the sulfonylurea receptor (SUR) component of...