Abstract
Estrogenic steroids and adenosine A2A receptors promote the wound healing and angiogenesis processes. However, so far, it is unclear whether estrogen may regulate the expression and pro-angiogenic activity of A2A receptors. Using in vivo analyses, we showed that female wild type (WT) mice have a more rapid wound healing process than female or male A2A-deficient mice (A2AKO) mice. We also found that pulmonary endothelial cells (mPEC) isolated from female WT mice showed higher expression of A2A receptor than mPEC from male WT mice. mPEC from female WT mice were more sensitive to A2A-mediated pro-angiogenic response, suggesting an ER and A2A crosstalk, which was confirmed using cells isolated from A2AKO. In those female cells, 17β-estradiol potentiated A2A-mediated cell proliferation, an effect that was inhibited by selective antagonists of estrogen receptors (ER), ERα, and ERβ. Therefore, estrogen regulates the expression and/or pro-angiogenic activity of A2A adenosine receptors, likely involving activation of ERα and ERβ receptors. Sexual dimorphism in wound healing observed in the A2AKO mice process reinforces the functional crosstalk between ER and A2A receptors.
Highlights
A substantial body of evidence describes contrasting influences of androgenic and estrogenic sex steroids on the healing of acute skin wounds, in which the former inhibits whereas the latter accelerates recovery [1]
No significant differences were observed between female and male wild type (WT) or female and male A2AKO mice, female WT and female A2AKO mice tend to have a faster wound healing process compared to their respective male counterparts
We showed that female mPEC has a higher expression of A2A receptors. 17β-estradiol enhanced the endothelial cell proliferation induced by A2A-stimulation, an effect more likely to be associated with the activation of both ERα and ERβ receptors
Summary
A substantial body of evidence describes contrasting influences of androgenic and estrogenic sex steroids on the healing of acute skin wounds, in which the former inhibits whereas the latter accelerates recovery [1]. Among many cell actors in the angiogenesis process, endothelial cells (ECs) have an essential role for new vessel formation via an increase in cell proliferation, migration, and tube formation capacity [5]. An increasing body of evidence indicates sexual dimorphism in endothelial cell function and in the angiogenesis process [6,7]. 17β-estradiol enhances proliferation, migration, and tube formation of endothelial cells, an effect likely involving the activation of the vascular endothelial growth factor (VEGF) and ERα pathways [9]
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