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Accelerated atherosclerosis leading to heart attack and stroke are the major causes of death in these patients. Endothelial cell (EC) dysfunction contributes to the pathogenesis of HGPS related cardiovascular diseases (CVD). Endothelial cell\u2013cell communications are important in the development of the vasculature, and their disruptions contribute to cardiovascular pathology. However, it is unclear how progerin interferes with such communications that lead to vascular dysfunction. An antibody array screening of healthy and HGPS patient EC secretomes identified Angiopoietin\u20102 (Ang2) as a down\u2010regulated signaling molecule in HGPS ECs. A similar down\u2010regulation of <jats:italic>Ang2<\/jats:italic> mRNA and protein was detected in the aortas from an HGPS mouse model. Addition of Ang2 to HGPS ECs rescues vasculogenesis, normalizes endothelial cell migration and gene expression, and restores nitric oxide bioavailability through eNOS activation. Furthermore, Ang2 addition reverses unfavorable paracrine effects of HGPS ECs on vascular smooth muscle cells. Lastly, by utilizing adenine base editor (ABE)\u2010corrected HGPS ECs and progerin\u2010expressing HUVECs, we demonstrated a negative correlation between progerin and Ang2 expression. Lastly, our results indicated that Ang2 exerts its beneficial effect in ECs through Tie2 receptor binding, activating an Akt\u2010mediated pathway. Together, these results provide molecular insights into EC dysfunction in HGPS and suggest that Ang2 treatment has potential therapeutic effects in HGPS\u2010related CVD.<\/jats:p>","DOI":"10.1111\/acel.14375","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T10:03:32Z","timestamp":1729245812000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Angiopoietin\u20102 reverses endothelial cell dysfunction in progeria vasculature"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-3288","authenticated-orcid":false,"given":"Sahar","family":"Vakili","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics University of Maryland  College Park Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth K.","family":"Izydore","sequence":"additional","affiliation":[{"name":"Department of 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National Human Genome Research Institute National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Shores","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijing","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics University of Maryland  College Park Maryland USA"},{"name":"Frederick National Laboratory for Cancer Research  Frederick Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Erdos","sequence":"additional","affiliation":[{"name":"Molecular Genetics Section, Center for Precision Health Research, National Human Genome Research Institute National Institutes of Health  Bethesda Maryland 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