Journal Article

PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation

Hlushchuk, R, Uccelli, A, Bartolomeo, M, Heberer, M, Vollmar, B, Gürke, L, Butschkau, A, Djonov, V, Valente, P, Banfi, A, Schaefer, D J, Burger, M G, Certelli, A, Groppa, E, Gianni-Barrera, R

2018

Overview

VEGF induces normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo. This transition depends on the balance between VEGF-induced endothelial stimulation and PDGF-BB-mediated pericyte recruitment, and co-expression of PDGF-BB normalizes aberrant angiogenesis despite high VEGF doses. We recently found that VEGF over-expression induces angiogenesis in skeletal muscle through an initial circumferential vascular enlargement followed by longitudinal splitting, rather than sprouting. Here we investigated the cellular mechanism by which PDGF-BB co-expression normalizes VEGF-induced aberrant angiogenesis. Monoclonal populations of transduced myoblasts, expressing similarly high levels of VEGF alone or with PDGF-BB, were implanted in mouse skeletal muscles. PDGF-BB co-expression did not promote sprouting and angiogenesis that occurred through vascular enlargement and splitting. However, enlargements were significantly smaller in diameter, due to a significant reduction in endothelial proliferation, and retained pericytes, which were otherwise lost with high VEGF alone. A time-course of histological analyses and repetitive intravital imaging showed that PDGF-BB co-expression anticipated the initiation of vascular enlargement and markedly accelerated the splitting process. Interestingly, quantification during in vivo imaging suggested that a global reduction in shear stress favored the initiation of transluminal pillar formation during VEGF-induced splitting angiogenesis. Quantification of target gene expression showed that VEGF-R2 signaling output was significantly reduced by PDGF-BB co-expression compared to VEGF alone. In conclusion, PDGF-BB co-expression prevents VEGF-induced aberrant angiogenesis by modulating VEGF-R2 signaling and endothelial proliferation, thereby limiting the degree of circumferential enlargement and enabling efficient completion of vascular splitting into normal capillary networks despite high VEGF doses.

• Publisher: Springer Nature B.V
• Subject: Aberration / Angiogenesis / Constraining / Enlargement / Expansion / Gene expression / Kinases / Mechanical stimuli / Muscles / Musculoskeletal system / Myoblasts / Overexpression / Pericytes / Platelet-derived growth factor / Platelet-derived growth factor BB / Reduction / Shear stress / Signaling / Skeletal muscle / Splitting / Surgical implants / Vascular endothelial growth factor / Vascular endothelial growth factor receptors