Abstract
Angiogenesis is an essential process during tissue regeneration; however, the amount of angiogenesis directly correlates with the level of wound scarring. Angiogenesis is lower in scar-free foetal wounds while angiogenesis is raised and abnormal in pathophysiological scarring such as hypertrophic scars and keloids. Delineating the mechanisms that modulate angiogenesis and could reduce scarring would be clinically useful. Beta-adrenoceptors (β-AR) are G protein-coupled receptors (GPCRs) expressed on all skin cell-types. They play a role in wound repair but their specific role in angiogenesis is unknown. In this study, a range of in vitro assays (single cell migration, scratch wound healing, ELISAs for angiogenic growth factors and tubule formation) were performed with human dermal microvascular endothelial cells (HDMEC) to investigate and dissect mechanisms underpinning β-AR-mediated modulation of angiogenesis in chick chorioallantoic membranes (CAM) and murine excisional skin wounds. β-AR activation reduced HDMEC migration via cyclic adenosine monophosphate (cAMP)-dependent and protein kinase A (PKA)-independent mechanisms as demonstrated through use of an EPAC agonist that auto-inhibited the cAMP-mediated β-AR transduced reduction in HDMEC motility; a PKA inhibitor was, conversely, ineffective. ELISA studies demonstrated that β-AR activation reduced pro-angiogenic growth factor secretion from HDMECs (fibroblast growth factor 2) and keratinocytes (vascular endothelial growth factor A) revealing possible β-AR-mediated autocrine and paracrine anti-angiogenic mechanisms. In more complex environments, β-AR activation delayed HDMEC tubule formation and decreased angiogenesis both in the CAM assay and in murine excisional skin wounds in vivo. β-AR activation reduced HDMEC function in vitro and angiogenesis in vivo; therefore, β-AR agonists could be promising anti-angiogenic modulators in skin. J. Cell. Physiol. 230: 356–365, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.
Highlights
Angiogenesis is the formation of new blood vessels from pre-existing post capillary venules; it plays an important role in development, tissue regeneration and tumour growth
Our initial finding that all three β-AR subtypes are expressed by primary human dermal microvascular endothelial cells (HDMEC) (Figure 1) further complements previous research exploring β-AR expression in endothelial cells (Howell et al, 1988) and provided us with the stimulus to investigate the role that the β-ARs and their signalling networks might play in modulating the functional behaviour of this cell type. β-AR activation was found to be anti-motogenic, decreasing HDMEC single cell migration (Figure 2) and scratch wound healing (Figure 3)
ELISA studies demonstrated that β-AR activation reduced fibroblast growth factor (FGF)-2 secretion from HDMECs and Vascular endothelial growth factor (VEGF)-A secretion from keratinocytes (Figure 5)
Summary
Angiogenesis is the formation of new blood vessels from pre-existing post capillary venules; it plays an important role in development, tissue regeneration and tumour growth. Endothelial cells (EC) differentiate and detach from adjacent capillaries, proliferate and migrate directionally. Angiogenesis is essential for wound repair (Falanga, 2005) and the amount of wound angiogenesis directly correlates with the level of scarring (van der Veer et al, 2011). Vascular endothelial growth factor (VEGF)-A addition to wounds promotes scarring and levels of VEGF and angiogenesis are lower in scar-free fetal wounds (Wilgus et al, 2008) and non-scarring oral wounds (Szpaderska et al, 2005). Persists, in hypertrophic scars from 12 weeks postoperatively (van der Veer et al, 2011) and in keloid scars (Mogili et al, 2012). The mechanisms by which β-ARs modulate dermal EC function in the angiogenic process during skin wound healing have largely been unexplored
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