Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential

Clément D’audigier (1, 2, 3) , Benoit Gautier (4, 1) , Alexis Yon (1, 2) , Jean-Meidi Alili (1, 2) , Coralie L. Guérin (1, 2) , Solène M. Evrard (1, 2, 3) , Anne Godier (1, 2, 5) , Skerdi Haviari (1, 2) , Marie Reille-Serroussi (1, 4) , Florent Huguenot (1, 4) , Blandine Dizier (1, 2) , Nicolas Inguimbert (6) , Delphine Borgel (7) , Ivan Bièche (8) , Catherine Boisson-Vidal (1, 2) , Carmen Roncal (9) , Peter Carmeliet (9) , Michel Vidal (10, 1, 4) , Pascale Gaussem (1, 2, 3, 11) , David M. Smadja (1, 2, 3)

1 USPC - Université Sorbonne Paris Cité
2 UMR_S 765 - Thrombose : Épidémiologie, Physiopathologie et Thérapeutiques Innovantes
3 Service d’hématologie biologique
4 COMETE - UMR 8638 - Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale
5 Service d`anesthésie et réanimation
6 LCBE - Laboratoire de Chimie des Biomolécules et de l'Environnement
7 Faculté de Pharmacie
8 Inserm U745 - Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux
9 Laboratory of Angiogenesis and Neurovascular Link
10 Hôpital Cochin [AP-HP]
11 U765 - Risque Thrombotique et Mécanismes de l'Hémostase

Objectives We studied whether plasma levels of angiogenic factors VEGF and placental growth factor (PlGF) in coronary artery disease patients or undergoing cardiac surgery are modified, and whether those factors modulate endothelial progenitor’s angiogenic potential. Methods and results A total of 143 patients’ plasmas from two different studies were analyzed (30 coronary artery disease patients, 30 patients with stable angina, coupled with 30 age and sex-matched controls; 53 patients underwent cardiac surgery). Among factors screened, only PlGF was found significantly increased in these pathological populations. PlGF-1 and PlGF-2 were then tested on human endothelial-colony-forming cells (ECFCs). We found that PlGF-1 and PlGF-2 induce VEGFR1 phosphorylation and potentiate ECFCs tubulogenesis in vitro. ECFCs VEGFR1 was further inhibited using a specific small interfering RNA (siRNA) and the chemical compound 4321. We then observed that the VEGFR1-siRNA and the compound 4321 decrease ECFCs tubulogenesis potential in vitro. Finally, we tested the compound 4321 in the preclinical Matrigel®-plug model with C57Bl/6J mice as well as in the murine hindlimb ischemia model. We found that 4321 inhibited the plug vascularization, attested by the hemoglobin content and the VE-Cadherin expression level and that 4321 inhibited the post-ischemic revascularization. Conclusion PlGF plasma levels were found increased in cardiovascular patients. Disrupting PlGF/VEGFR1 pathway could modulate ECFC-induced tubulogenesis, the cell type responsible for newly formed vessels in vivo.

Mots clés: Biomarker; Placental growth factor; Endothelial progenitor cells; Endothelial-colony-forming cells; VEGFR1

Domaines: Sciences du Vivant [q-bio]

Clément D’audigier, Benoit Gautier, Alexis Yon, Jean-Meidi Alili, Coralie L. Guérin, et al.. Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential. Angiogenesis, 2014, 17 (3), p. 603-616. ⟨10.1007/s10456-013-9413-2⟩. ⟨hal-01300965⟩