{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T17:42:36Z","timestamp":1786210956595,"version":"build-2736575974"},"reference-count":67,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"crossref","award":["HT9425-24-1-0131"],"award-info":[{"award-number":["HT9425-24-1-0131"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["DK136814"],"award-info":[{"award-number":["DK136814"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Advances in Wound Care"],"abstract":"<jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>Ischemic tissue perfusion remains a major clinical challenge despite VEGF\u2019s central role in angiogenesis. Limited success of VEGF-based therapies underscores the need to understand endothelial heterogeneity, as distinct subsets exhibit differential responsiveness. This study explores conserved endothelial states that govern VEGF-driven angiogenesis across human organs and evaluates their functional significance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach:<\/jats:title>\n                    <jats:p>We performed single-cell and single-nucleus RNA-sequencing (scRNA-seq\/snRNA-seq) analysis of endothelial cells (ECs) from eight human tissues using GTEx data, validated findings in independent skin and heart datasets, and conducted CRISPR-mediated PLC\u03b32 knockout in cultured ECs followed by scRNA-seq.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Analysis of 209,126 nuclei revealed a universal arterial-like endothelial subset (cluster 2) enriched across all organs, characterized by high expression of\n                      <jats:italic toggle=\"yes\">PLC\u03b32<\/jats:italic>\n                      , a critical VEGF signaling effector.\n                      <jats:italic toggle=\"yes\">PLC\u03b32<\/jats:italic>\n                      <jats:sup>high<\/jats:sup>\n                      cells exhibited robust angiogenic and lymphangiogenic programs, including upregulation of\n                      <jats:italic toggle=\"yes\">VEGFC<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">NOTCH4<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">JAG1<\/jats:italic>\n                      , and enrichment of pathways for vasculature development and endothelial differentiation. Cell\u2013cell communication analysis demonstrated exclusive BMP6, IGF2, and CXCL12 signaling from\n                      <jats:italic toggle=\"yes\">PLC\u03b32<\/jats:italic>\n                      <jats:sup>high<\/jats:sup>\n                      cells to fibroblasts, pericytes, and immune cells, positioning this subset as a central angiogenic hub. Functional validation showed that PLC\u03b32 knockout depleted\n                      <jats:italic toggle=\"yes\">PLC\u03b32<\/jats:italic>\n                      <jats:sup>high<\/jats:sup>\n                      clusters, suppressed VEGF signaling, and diminished BMP6 ligand secretion, confirming its role in maintaining proangiogenic endothelial states.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:<\/jats:title>\n                    <jats:p>\n                      Ineffective targeting of the appropriate EC state may limit current therapeutic VEGF strategies, positioning\n                      <jats:italic toggle=\"yes\">PLC\u03b32<\/jats:italic>\n                      <jats:sup>high<\/jats:sup>\n                      ECs as a clinically relevant target.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      We identify\n                      <jats:italic toggle=\"yes\">PLC\u03b32<\/jats:italic>\n                      <jats:sup>high<\/jats:sup>\n                      arterial ECs as a conserved pan-organ population critical for VEGF responsiveness and vascular regeneration. These findings reimagine VEGF therapy by highlighting PLC\u03b32 as a critical regulator of a proangiogenic arterial-like endothelial state and a promising combinatorial target to overcome limitations of current angiogenic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/21621918261474733","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T02:39:53Z","timestamp":1785897593000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reimagining VEGF Therapy: The Role of PLC\u03b32 in Pan-Organ Endothelial Networks"],"prefix":"10.1177","author":[{"given":"Ahmed S.","family":"Abouhashem","sequence":"first","affiliation":[{"name":"Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA."},{"name":"Sharkia Clinical Research Department, Ministry of Health and Population, Zagazig, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumit S.","family":"Verma","sequence":"additional","affiliation":[{"name":"Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Faden-McCormack","sequence":"additional","affiliation":[{"name":"Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yomna A.","family":"Moqidem","sequence":"additional","affiliation":[{"name":"School of Biological Science, Faculty of Environmental and life sciences, University of Southampton, Southampton, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Partha","family":"Dutta","sequence":"additional","affiliation":[{"name":"Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3151-5202","authenticated-orcid":false,"given":"Chandan K.","family":"Sen","sequence":"additional","affiliation":[{"name":"Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-9618","authenticated-orcid":false,"given":"Kanhaiya","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/21621918251366681"},{"key":"e_1_3_3_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2009.70"},{"key":"e_1_3_3_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000527079"},{"key":"e_1_3_3_5_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20212539"},{"key":"e_1_3_3_6_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210565"},{"key":"e_1_3_3_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.36"},{"issue":"10","key":"e_1_3_3_8_1","first-page":"3527","article-title":"Endothelial cells in physiology and in the pathophysiology of vascular disorders","volume":"91","author":"Cines DB","year":"1998","unstructured":"7.Cines DB, , Pollak ES, , Buck CA, et al. 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