Lymphatic endothelial cell-specific A2AR knockout in mice fed a high-salt diet increased blood pressure by 17% and skin sodium content by 17% compared to wild-type mice.
Does A2AR activation reduce blood pressure and improve lymphangiogenesis in salt-sensitive hypertension models?
A2AR activation promotes dermal lymphangiogenesis and reduces blood pressure in salt-sensitive hypertension via a novel VEGF-independent VEGFR2 signaling pathway.
AIMS: Excess dietary sodium intake and retention lead to hypertension. Impaired dermal lymphangiogenesis and lymphatic dysfunction-mediated sodium and fluid imbalance are pathological mechanisms. The adenosine A2A receptor (A2AR) is expressed in lymphatic endothelial cells (LECs), while the roles and mechanisms of LEC-A2AR in skin lymphangiogenesis during salt-induced hypertension are not clear. METHODS AND RESULTS: The expression of LEC-A2AR correlated with lymphatic vessel density in both high-salt diet (HSD)-induced hypertensive mice and hypertensive patients. Lymphatic endothelial cell-specific A2AR knockout mice fed HSD exhibited 17 ± 2% increase in blood pressure and 17 ± 3% increase in Na+ content associated with decreased lymphatic density (-19 ± 2%) compared with HSD-WT mice. A2AR activation by agonist CGS21680 increased lymphatic capillary density and decreased blood pressure in HSD-WT mice. Furthermore, this A2AR agonist activated MSK1 directly to promote VEGFR2 activation and endocytosis independently of VEGF as assessed by phosphoprotein profiling and immunoprecipitation assays in LECs. VEGFR2 kinase activity inhibitor fruquintinib or VEGFR2 knockout in LECs but not VEGF-neutralizing antibody bevacizumab suppressed A2AR activation-mediated decrease in blood pressure. Immunostaining revealed phosphorylated VEGFR2 and MSK1 expression in the LECs were positively correlated with skin lymphatic vessel density and A2AR level in hypertensive patients. CONCLUSION: The study highlights a novel A2AR-mediated VEGF-independent activation of VEGFR2 signaling in dermal lymphangiogenesis and sodium balance, which might be a potential therapeutic target in salt-sensitive hypertension.
Zhuang et al. (Wed,) conducted a other in Salt-sensitive hypertension. A2AR knockout / A2AR agonist (CGS21680) vs. Wild-type / Vehicle was evaluated on Blood pressure and skin sodium content. Lymphatic endothelial cell-specific A2AR knockout in mice fed a high-salt diet increased blood pressure by 17% and skin sodium content by 17% compared to wild-type mice.