1. Academic Validation
  2. D-Peptide analogues of Boc-Phe-Leu-Phe-Leu-Phe-COOH induce neovascularization via endothelial N-formyl peptide receptor 3

D-Peptide analogues of Boc-Phe-Leu-Phe-Leu-Phe-COOH induce neovascularization via endothelial N-formyl peptide receptor 3

  • Angiogenesis. 2020 Aug;23(3):357-369. doi: 10.1007/s10456-020-09714-0.
Mohd I Nawaz 1 2 Sara Rezzola 1 Chiara Tobia 1 Daniela Coltrini 1 Mirella Belleri 1 Stefania Mitola 1 Michela Corsini 1 Annamaria Sandomenico 3 Andrea Caporale 3 4 Menotti Ruvo 3 5 Marco Presta 6 7
Affiliations

Affiliations

  • 1 Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
  • 2 Department of Ophthalmology, King Saud University, Riyadh, Kingdom of Saudi Arabia.
  • 3 Istituto Di Biostrutture e Bioimmagini, CNR, Napoli, Italy.
  • 4 Istituto Di Cristallografia, CNR, Trieste, Italy.
  • 5 AnBition srl, Napoli, Italy.
  • 6 Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. marco.presta@unibs.it.
  • 7 Italian Consortium for Biotechnology (CIB), Unit of Brescia, Trieste, Italy. marco.presta@unibs.it.
Abstract

N-formyl peptide receptors (FPRs) are G protein-coupled receptors involved in the recruitment and activation of immune cells in response to pathogen-associated molecular patterns. Three FPRs have been identified in humans (FPR1-FPR3), characterized by different ligand properties, biological function and cellular distribution. Recent findings from our laboratory have shown that the peptide BOC-FLFLF (L-BOC2), related to the FPR antagonist BOC2, acts as an angiogenesis inhibitor by binding to various angiogenic growth factors, including vascular endothelial growth factor-A165 (VEGF). Here we show that the all-D-enantiomer of L-BOC2 (D-BOC2) is devoid of any VEGF antagonist activity. At variance, D-BOC2, as well as the D-FLFLF and succinimidyl (Succ)-D-FLFLF (D-Succ-F3) D-peptide variants, is endowed with a pro-angiogenic potential. In particular, the D-peptide D-Succ-F3 exerts a pro-angiogenic activity in a variety of in vitro assays on human umbilical vein endothelial cells (HUVECs) and in ex vivo and in vivo assays in chick and zebrafish embryos and adult mice. This activity is related to the capacity of D-Succ-F3 to bind FRP3 expressed by HUVECs. Indeed, the effects exerted by D-Succ-F3 on HUVECs are fully suppressed by the G protein-coupled receptor inhibitor pertussis toxin, the FPR2/FPR3 antagonist WRW4 and by an anti-FPR3 antibody. A similar inhibition was observed following WRW4-induced FPR3 desensitization in HUVECs. Finally, D-Succ-F3 prevented the binding of the anti-FPR3 antibody to the cell surface of HUVECs. In conclusion, our data demonstrate that the angiogenic activity of D-Succ-F3 is due to the engagement and activation of FPR3 expressed by endothelial cells, thus shedding a new LIGHT on the biological function of this chemoattractant receptor.

Keywords

Angiogenesis; BOC2; D-Peptide; Formyl peptide receptor; Huvecs.

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