Therapeutic Potential of PlGF in Ischemic Cardiac Diseases

Cardiac ischemia represents an imbalance between the demand and supply of oxygen-rich blood to the myocardium. Coronary blood support may decrease gradually due to atherosclerosis or it may decrease abruptly as a result of a thrombotic event. While gradual reduction of the coronary lumen by atherosclerosis will manifest by angina pectoris, sudden occlusion will result in acute coronary syndrome. Despite major progress in prevention and early intervention, coronary artery disease remains a leading cause of mortality and morbidity.  The therapy comprises  improvement of flow by pharmacological or mechanical vasodilation, thrombus removal, bypass surgery or more chronically by vascular remodeling, which includes collateral development. In the case of chronic or acute occlusion of a major artery, preexisting arteriolar connections can be recruited to bypass the site of occlusion.

Placental growth factor (PlGF), a member of the vascular endothelial growth factor family has a pleiotropic role in angiogenesis and vasculogenesis. PlGF exerts its function via vascular endothelial growth factor receptor 1 (VEGFR-1). Moreover, due to the presence of a heparin-binding domain, PlGF-2 can bind to neuropilin-1 and -2 co-receptors with consequent enhanced signaling. PlGF directly facilitates the proliferation, migration and survival of endothelial cells, proliferation of mesenchymal fibroblasts, and recruitment of myeloid progenitors and smooth muscle cells during collateral growth. It indirectly stimulates non-vascular cells, capable to release proangiogenic factors. PlGF does not affect quiescent vessels in healthy organs and its expression is up-regulated following ischemia.

CoBioRes wants to provide an alternative and clinically relevant strategy to boost cardiac angio- and arteriogenesis using a recombinant human PlGF-2–based (rhPlGF-2) protein therapy to target chronic ischemic cardiomyopathy.

Preclinical research is performed in close collaboration with the group of Prof. Stefan Janssens at the Department of Cardiovascular Sciences (KU Leuven).

The crystal structure of the ligand-induced VEGFR-1 extracellular domain dimer (blue) with PlGF in the binding pocket (green)

References:

http://ajpheart.physiology.org/content/304/6/H885
http://www.sciencedirect.com/science/article/pii/S0167527315307415

Protein Database (PDB) code: 1RV6
Bry M et al. Physiol Rev 2014;94:779-794
Hoffmann DC et al. J Biol Chem. 2011;286:28889-28901