2. Academic Validation
  3. Peptidylarginine Deiminases Inhibitors Decrease Endothelial Cells Angiogenic Potential by Affecting Akt Signaling and the Expression and Secretion of Angiogenic Factors

Peptidylarginine Deiminases Inhibitors Decrease Endothelial Cells Angiogenic Potential by Affecting Akt Signaling and the Expression and Secretion of Angiogenic Factors

  • Cell Physiol Biochem. 2024 Feb 19;58(1):63-82. doi: 10.33594/000000683.
Oskar Ciesielski 1 2,  Luciano Pirola 3,  Aneta Balcerczyk 4
Affiliations

Affiliations

  • 1 Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, Lodz 90-236, Poland.
  • 2 The Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.
  • 3 CarMeN Laboratory, INSERM Unit 1060, Lyon-1 University, 165 Chemin du Grand Revoyet, BP12, 69495, Pierre Bénite Cedex, France.
  • 4 Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, Lodz 90-236, Poland, [email protected].
PMID: 38374715 DOI: 10.33594/000000683
Abstract

Background/aims: Endothelial cells (ECs) play a crucial role in various physiological processes, particularly those related to the cardiovascular system, but also those affecting the entire organism. The biology of ECs is regulated by multiple biochemical stimuli and epigenetic drivers that govern gene expression. We investigated the angiogenic potential of ECs from a protein citrullination perspective, regulated by peptidyl-arginine deiminases (PADs) that modify histone and non-histone proteins. Although the involvement of PADs has been demonstrated in several physiological processes, inflammation-related disorders and Cancer, their role in angiogenesis remains unclear.

Methods: To elucidate the role of PADs in endothelial angiogenesis, we used two human EC models: primary vein (HUVECs) and microvascular endothelial cells (HMEC-1). PADs activity was inhibited using irreversible inhibitors: BB-Cl-amidine, Cl-amidine and F-amidine. We analyzed all three steps of angiogenesis in vitro : proliferation, migration, and capillary-like tube formation, as well as secretory activities, gene expression and signaling in ECs.

Results: All used PAD inhibitors reduced the histone H3 citrullination (H3cit) mark, inhibited endothelial cell migration and capillary-like tube formation, and favored an angiostatic activity in HMEC-1 cells, by increasing PEDF (pigment epithelium-derived factor) and reducing VEGF (vascular endothelial growth factor) mRNA expression and protein secretion. Additionally, BB-Cl-amidine reduced the total activity of MMPs (Matrix Metalloproteinases). The observed effects were underlined by the inhibition of Akt phosphorylation.>.

Conclusion: Our findings suggest that pharmacological inhibitors of citrullination are promising therapeutic agents to target angiogenesis.

Keywords

Citrullination ; PADs inhibitors ; Endothelial cells ; Angiogenesis ; Akt signaling.

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