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Although vascular injury is a well-established trigger, accumulating evidence implicates hypoxia as an additional determinant of thrombus development. In our previous study, we demonstrated that hypoxia associated with high altitude can promote autophagy-induced platelet aggregation. However, the contribution of ECs to such thrombosis under comparable hypoxic conditions (10%) remains poorly understood. In this study, using ECs isolated from rat aorta ex vivo, we show that hypoxia-inducible factor-1 alpha (HIF-1\u03b1), a key transcription factor, regulates autophagy and subsequent EC activation. Importantly, pharmacological inhibition of HIF-1\u03b1-mediated autophagy, repositioning the FDA-approved drug chloroquine (CQ), led to attenuated expression of P-Selectin, ICAM1, VCAM1 and consequent reduced platelet adhesion to ECs. Further mechanistic analysis revealed that autophagy modulates the NF-\u03baB signaling pathway, in which P65 transcriptionally regulates the adhesion molecules ICAM1 and VCAM1 by binding to their upstream promoter elements under hypoxic conditions. In addition, using a rat IVC ligation model, we found that CQ not only attenuates thrombus formation but also suppresses VCAM1 expression, validating its antithrombotic potential. In summary, our findings suggest that hypoxia-induced HIF-1\u03b1 activation promotes an autophagy-dependent NF-\u03baB signaling cascade, thereby contributing to endothelial activation and thrombus formation. Furthermore, CQ\u2019s ability to disrupt this pathway underscores the therapeutic potential of targeting endothelial autophagy to mitigate hypoxia-associated thrombosis.<\/jats:p>","DOI":"10.1021\/acsptsci.5c00770","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:17:53Z","timestamp":1785849473000},"page":"2184-2197","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological\nBlockade of Hypoxia-Driven Autophagy:\nA Therapeutic Strategy to Limit Endothelial Activation and Thrombosis"],"prefix":"10.1021","volume":"9","author":[{"given":"Propanna","family":"Bandyopadhyay","sequence":"first","affiliation":[{"name":"BITS Pilani , , Pilani Campus , ,","place":["Rajasthan, India, 333031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9125-6727","authenticated-orcid":true,"given":"Pragati Ramesh","family":"Kumbhar","sequence":"additional","affiliation":[{"name":"BITS Pilani , , Pilani Campus , ,","place":["Rajasthan, India, 333031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5390-5925","authenticated-orcid":true,"given":"Yash T.","family":"Katakia","sequence":"additional","affiliation":[{"name":"BITS Pilani , , Pilani Campus , ,","place":["Rajasthan, India, 333031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syamantak","family":"Majumder","sequence":"additional","affiliation":[{"name":"BITS Pilani , , Pilani Campus , ,","place":["Rajasthan, India, 333031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7731-1873","authenticated-orcid":true,"given":"Sudeshna","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"BITS Pilani , , Pilani Campus , ,","place":["Rajasthan, India, 333031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9706-9244","authenticated-orcid":true,"given":"Gautam","family":"Singhvi","sequence":"additional","affiliation":[{"name":"BITS Pilani , , Pilani Campus , ,","place":["Rajasthan, India, 333031"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajdeep","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"BITS Pilani , , Pilani Campus , ,","place":["Rajasthan, India, 333031"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"issue":"1","key":"2026081411073762900_cit1","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1186\/s12872-015-0124-z","article-title":"Endothelial cell control of thrombosis","volume":"15","author":"Yau","year":"2015","journal-title":"BMC\nCardiovasc. 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