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Background and purpose: The thromboxane A2 receptor (TP) plays an eminent role in the pathophysiology of endothelial dysfunction and cardiovascular disease. Moreover, its expression is reported to increase in the intimal layer of blood vessels of cardiovascular high-risk individuals. Yet it is unknown, whether TP upregulation per se has the potential to affect the homeostasis of the vascular endothelium. Experimental approach and key results: Here we report that increasing endothelial expression of both human TP isoforms induces endothelial cell tension and aberrant cell morphology, affects focal adhesion dynamics and inhibits the angiogenic capacity of human endothelial cells in vitro and in vivo, whereas TP knockdown exerts opposing effects. Combined global transcriptome, lipidomic, functional live-cell and validating expression analyses reveal that endothelial TP upregulation induces cyclooxygenase-2 in a Gi/o and Gq/11-dependent manner, thereby promoting its own activation via the auto/paracrine release of TP agonists, such as prostaglandin H2 or prostaglandin F2 but not thromboxane A2. Consequently, this TP-dependent angiostatic feedback loop is disrupted by pharmacological TP or cyclooxygenase-2 inhibition and by genetic reconstitution of prostaglandin H2-metabolizing prostacyclin synthase even in the absence of functional prostacyclin receptor expression. Further mechanistic analyses of downstream TP effectors disclose that the TP induces endothelial cell tension, focal adhesion dysregulation and angiostatic effects via a ROCK-LIMK2-myosin II-dependent signal transduction pathway and downregulates important mediators of endothelial cell homeostasis, e.g. VEGFR-2. Conclusions and implications: Our work uncovers a previously unrecognized mechanism, by which pathological endothelial upregulation of the TP could directly foster endothelial dysfunction, vascular rarefaction and systemic hypertension.