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The vascular endothelial thromboxane A2/prostaglandin H2 receptor controls its own activation and impairs angiogenesis via an autocrine cyclooxygenase-2-dependent positive feedback loop.

ABSTRACT: The thromboxane A2/prostaglandin H2 receptor (TP) plays an eminent role in the pathogenesis of cardiovascular disease and its expression has been reported to increase in the dysfunctional endothelium of cardiovascular high-risk patients. Yet it remains enigmatic in which way the vascular endothelial TP affects angiogenesis. Here we show that increased endothelial TP expression, in the absence of exogenous TP agonists, profoundly inhibits, whereas TP knockdown or endothelial-specific knockout enhance the angiogenic capacity of vascular endothelial cells in vitro and in vivo. Global transcriptome, lipidomic, and functional analyses reveal that the TP induces endothelial cyclooxygenase-2 and downregulates prostacyclin synthase to promote TP ligand release, persistent TP activation, suppression of VEGFR2 expression and inhibition of angiogenesis, effects that are reversed by pharmacological TP inhibition or prostacyclin synthase reconstitution. Further mechanistic analyses reveal that endothelial TP increase cell tension, disturb focal adhesion dynamics and inhibit migration, tube formation and angiogenic sprouting via pathways that enhance endothelial actomyosin contractility. In conclusion, our work uncovers an anti-angiogenic feedback loop by which the TP may disturb angiogenesis and vascular endothelial homeostasis in disease states associated with increased TP expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146888 | GEO | 2022/03/01

REPOSITORIES: GEO

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