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Inherited loss-of-function (LOF) mutations in endoglin, encoding an endothelial cell (EC) expressed co-receptor for BMP9\/10, causes the disease HHT1\/Osler-Weber-Rendu, characterized by bleeding and AVMs. Here we observe increased activity of the downstream signalling complex mTORC1 within the retinal vasculature of HHT mouse models. To investigate its importance in AVM biology, concerning subvascular action, cell specificity, signalling strength and kinetics we combine timed genetic and antibody-based models of HHT with genetic mTORC1 inhibition or activation through EC specific deletion of\n                    <jats:italic>Rptor<\/jats:italic>\n                    or\n                    <jats:italic>Tsc1<\/jats:italic>\n                    . Results demonstrate that EC mTORC1 activation is secondary to endoglin LOF and mainly a consequence of systemic effects following AVM. While genetic EC inhibition of mTORC1 only showed tendencies towards reduced AVM severity, EC overactivation counterintuitively reduced it, implying that mTORC1 must be within a certain range to facilitate AVM. Complete inhibition of mTORC1 signalling by rapamycin provided the strongest therapeutic effect, pointing to potential involvement of RAPTOR-independent pathways or AVM-promoting effects of non-ECs in this pathology.\n                  <\/jats:p>","DOI":"10.1007\/s10456-024-09961-5","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T15:51:55Z","timestamp":1733932315000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genetic and pharmacological targeting of mTORC1 in mouse models of arteriovenous malformation expose non-cell autonomous signalling in HHT"],"prefix":"10.1007","volume":"28","author":[{"given":"Antonio","family":"Queiro-Palou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7956-587X","authenticated-orcid":false,"given":"Lars","family":"Jakobsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,11]]},"reference":[{"key":"9961_CR1","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1161\/CIRCRESAHA.119.315974","volume":"126","author":"S Tual-Chalot","year":"2020","unstructured":"Tual-Chalot S, Garcia-Collado M, Redgrave RE, Singh E, Davison B, Park C, Lin H, Luli S, Jin Y, Wang Y et al (2020) Loss of endothelial endoglin promotes high-output heart failure through Peripheral Arteriovenous shunting driven by VEGF signaling. 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