{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:24:09Z","timestamp":1791563049389,"version":"4.3.4"},"reference-count":80,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>\n              Capillary malformation (CM) occurs sporadically and is associated with Sturge-Weber syndrome. The somatic mosaic mutation in\n              <jats:italic>GNAQ<\/jats:italic>\n              (c.548G&gt;A, p.R183Q) is enriched in endothelial cells (ECs) in skin CM and Sturge-Weber syndrome brain CM. Our goal was to investigate how the mutant G\u03b1q (G-protein \u03b1q subunit) alters EC signaling and disrupts capillary morphogenesis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>\n              We used lentiviral constructs to express p.R183Q or wild-type\n              <jats:italic>GNAQ<\/jats:italic>\n              in normal human endothelial colony forming cells (EC-R183Q and EC-WT, respectively). EC-R183Q constitutively activated PLC (phospholipase C) \u03b23, a downstream effector of G\u03b1q. Activated PLC\u03b23 was also detected in human CM tissue sections. Bulk RNA sequencing analyses of mutant versus wild-type EC indicated constitutive activation of PKC (protein kinase C), NF-\u03baB (nuclear factor kappa B) and calcineurin signaling in EC-R183Q. Increased expression of downstream targets in these pathways, ANGPT2 (angiopoietin-2) and DSCR (Down syndrome critical region protein) 1.4 were confirmed by quantitative PCR and immunostaining of human CM tissue sections. The G\u03b1q inhibitor YM-254890 as well as siRNA targeted to PLC\u03b23 reduced mRNA expression levels of these targets in EC-R183Q while the pan-PKC inhibitor AEB071 reduced ANGPT2 but not DSCR1.4. EC-R183Q formed enlarged blood vessels in mice, reminiscent of those found in human CM. shRNA knockdown of ANGPT2 in EC-R183Q normalized the enlarged vessels to sizes comparable those formed by EC-WT.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>G\u03b1q-R183Q, when expressed in ECs, establishes constitutively active PLC\u03b23 signaling that leads to increased ANGPT2 and a proangiogenic, proinflammatory phenotype. EC-R183Q are sufficient to form enlarged CM-like vessels in mice, and suppression of ANGPT2 prevents the enlargement. Our study provides the first evidence that endothelial G\u03b1q-R183Q is causative for CM and identifies ANGPT2 as a contributor to CM vascular phenotype.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.121.316651","type":"journal-article","created":{"date-parts":[[2021,10,21]],"date-time":"2021-10-21T09:00:20Z","timestamp":1634806820000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":59,"title":["Endothelial\n            <i>GNAQ<\/i>\n            p.R183Q Increases ANGPT2 (Angiopoietin-2) and Drives Formation of Enlarged Blood Vessels"],"prefix":"10.1161","volume":"42","author":[{"given":"Lan","family":"Huang","sequence":"first","affiliation":[{"name":"Vascular Biology Program (L.H., C.B., J.B.), Boston Children\u2019s Hospital and Harvard Medical School, MA."},{"name":"Department of Surgery (L.H., C.B., J.B.), Boston Children\u2019s Hospital and Harvard Medical School, 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