Mesoglycan connects Syndecan-4 and VEGFR2 through Annexin A1 and formyl peptide receptors to promote angiogenesis invitro.

Emanuela Pessolano,Amelia Filippelli,James Whiteford,Antonello Petrella,Raffaella Belvedere,Nunzia Novizio,Mauro Perretti

doi:10.1111/febs.16043

Emanuela Pessolano, Amelia Filippelli + Show 5 more

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https://doi.org/10.1111/febs.16043

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Abstract

Mesoglycan is a mixture of glycosaminoglycans (GAG) with fibrinolytic effects and the potential to enhance skin wound repair. Here, we have used endothelial cells isolated from wild‐type (WT) and Syndecan‐4 null (Sdc4‐/‐) C57BL/6 mice to demonstrate that mesoglycan promotes cell motility and in vitro angiogenesis acting on the co‐receptor Syndecan‐4 (SDC4). This latter is known to participate in the formation and release of extracellular vesicles (EVs). We characterized EVs released by HUVECs and assessed their effect on angiogenesis. Particularly, we focused on Annexin A1 (ANXA1) containing EVs, since they may contribute to tube formation via interactions with Formyl peptide receptors (FPRs). In our model, the bond ANXA1‐FPRs stimulates the release of vascular endothelial growth factor (VEGF‐A) that interacts with vascular endothelial receptor‐2 (VEGFR2) and activates the pathway enhancing cell motility in an autocrine manner, as shown by wound healing/invasion assays, and the induction of endothelial to mesenchymal transition (EndMT). Thus, we have shown for the first time that mesoglycan exerts its pro‐angiogenic effects in the healing process triggering the activation of the three interconnected molecular axis: mesoglycan‐SDC4, EVs‐ANXA1‐FPRs, and VEGF‐A‐VEGFR2.

Highlights

Mesoglycan represents a potential therapy for augmenting the healing of skin lesions
We have used endothelial cells isolated from Wild Type (WT) and Syndecan-4 null (Sdc4-/-) C57BL/6 mice to demonstrate that mesoglycan promotes cell motility and in vitro angiogenesis acting on the co-receptor Syndecan-4 (SDC4)
The bond ANXA1FPRs stimulates the release of vascular endothelial growth factor (VEGF-A) that interacts with vascular endothelial receptor-2 (VEGFR2) and activates the pathway enhancing cell motility in an autocrine manner, as shown by Wound-Healing/invasion assays, and the induction of Endothelial to Mesenchymal Transition (EndMT)

Summary

Introduction

Mesoglycan represents a potential therapy for augmenting the healing of skin lesions This GAG mixture can promote angiogenesis in vitro, improving the generation of capillary- like structures essential for wound repair process [1]. Angiogenesis is fundamental in many physiological and para-physiological processes, and in the context of skin lesions it plays a key role in providing the tissue with the necessary nutrients [2]. During this process, endothelial cells undergo the Endothelial-toMesenchymal Transformation (EndMT). Angiogenic capillaries infiltrate in the extracellular matrix (ECM) These cells arrange themselves into a microvascular network, produce granulation tissue [4], and lead to wound resolution resulting in healthy new skin. The formation of new vessels has a pivotal role in wound repair because the most common causes of the formation of chronic injuries are a poor perfusion of the wound which leads to a diminished bioavailability of growth factors and receptors and a decreased proliferative potential of the cells at the injury site [5]

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