A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.

Vascular-specific growth factors and blood vessel formation

Vascular endothelial growth factor (VEGF) is a fundamental regulator of normal and abnormal angiogenesis. Recent evidence indicates that VEGF is essential for embryonic vasculogenesis and angiogenesis. Furthermore, VEGF is required for the cyclical blood vessel proliferation in the female reproductive tract and for longitudinal bone growth and endochondral bone formation. Substantial experimental evidence also implicates VEGF in pathological angiogenesis. Anti-VEGF monoclonal antibodies or other VEGF inhibitors block the growth of many tumor cell lines in nude mice. Furthermore, the concentrations of VEGF are elevated in the aqueous and vitreous humors of patients with proliferative retinopathies such as the diabetic retinopathy. In addition, VEGF-induced angiogenesis results in a therapeutic benefit in several animal models of myocardial or limb ischemia. Currently, both therapeutic angiogenesis using recombinant VEGF or VEGF gene transfer and inhibition of VEGF-mediated pathological angiogenesis are being pursued.

Molecular and biological properties of vascular endothelial growth factor.

Promoting the formation of new collateral vessels in ischemic tissues using angiogenic growth factors (therapeutic angiogenesis) is a an exciting frontier of cardiovascular medicine. Conversely, inhibition of the action of key regulators of angiogenesis, such as VEGF, constitutes a promising approach for the treatment of solid tumors and intraocular neovascular syndromes. These concepts are being tested now in clinical trials.

Clinical applications of angiogenic growth factors and their inhibitors.

Background—We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia. Methods and Results—VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF165) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTx=75±15/min versus post-GTx=80±16/min, P=NS), systolic BP (114±7 versus 118±7 mm Hg, P=NS), or diastolic BP (57±2 versus 59±2 mm Hg, P=NS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm3, and total chest ...

Gene Therapy for Myocardial Angiogenesis : Initial Clinical Results With Direct Myocardial Injection of phVEGF165 as Sole Therapy for Myocardial Ischemia

Background— Recombinant human vascular endothelial growth factor protein (rhVEGF) stimulates angiogenesis in animal models and was well tolerated in Phase I clinical trials. VIVA (Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis) is a double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of intracoronary and intravenous infusions of rhVEGF. Methods and Results— A total of 178 patients with stable exertional angina, unsuitable for standard revascularization, were randomized to receive placebo, low-dose rhVEGF (17 ng · kg−1 · min−1), or high-dose rhVEGF (50 ng · kg−1 · min−1) by intracoronary infusion on day 0, followed by intravenous infusions on days 3, 6, and 9. Exercise treadmill tests, angina class, and quality of life assessments were performed at baseline, day 60, and day 120. Myocardial perfusion imaging was performed at baseline and day 60. At day 60, the change in exercise treadmill test (ETT) time from baseline was not different between groups...

The VIVA Trial Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis

A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study.

Results of intracoronary recombinant human vascular endothelial growth factor (rhVEGF) administration trial

Incidence and clinical significance of cardiac biomarker elevation during stem cell mobilization, apheresis, and intramyocardial delivery: An analysis from ACT34-CMI

Douglas W. Losordo

Papers

A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study.

Results of intracoronary recombinant human vascular endothelial growth factor (rhVEGF) administration trial

Incidence and clinical significance of cardiac biomarker elevation during stem cell mobilization, apheresis, and intramyocardial delivery: An analysis from ACT34-CMI

Impact of mobilization ability on cell functionality and comparison of normal and cmi subject samples: an analysis from act34–cmi