Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential

Area of Science:

• Cardiovascular Research
• Angiogenesis Biology
• Molecular Medicine

Background:

• Elevated angiogenic factors are implicated in cardiovascular disease.
• Understanding the role of placental growth factor (PlGF) in endothelial progenitor cell (ECFC) function is crucial for cardiovascular health.

Purpose of the Study:

• To investigate plasma levels of vascular endothelial growth factor (VEGF) and PlGF in patients with coronary artery disease (CAD) or undergoing cardiac surgery.
• To determine if PlGF modulates the angiogenic potential of ECFCs.

Main Methods:

• Plasma samples from 143 patients (CAD, stable angina, cardiac surgery) and controls were analyzed.
• PlGF-1 and PlGF-2 effects on human ECFCs were assessed in vitro, including VEGFR1 phosphorylation and tubulogenesis.
• VEGFR1 inhibition using siRNA and a small molecule (compound 4321) evaluated ECFC tubulogenesis.
• Compound 4321 efficacy was tested in preclinical mouse models (Matrigel plug, hindlimb ischemia).

Main Results:

• Placental growth factor (PlGF) levels were significantly increased in patients with coronary artery disease and those undergoing cardiac surgery compared to controls.
• PlGF-1 and PlGF-2 enhanced ECFC tubulogenesis in vitro by inducing VEGFR1 phosphorylation.
• Inhibition of VEGFR1 signaling via siRNA or compound 4321 reduced ECFC tubulogenesis.
• Compound 4321 inhibited vascularization in the Matrigel plug model and impaired revascularization in the hindlimb ischemia model.

Conclusions:

• Increased plasma PlGF levels are associated with cardiovascular disease states.
• Targeting the PlGF/VEGFR1 pathway offers a potential strategy to modulate ECFC-mediated neovascularization in cardiovascular conditions.