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Studies in arthritis, kidney disease, and cancer have demonstrated that dysregulation of the complement system can drive inflammation\u2010mediated tissue injury. We have shown that activation of the complement cascade, particularly the alternative pathway, within the pulmonary vasculature is a key driver of proinflammatory responses in pulmonary hypertension (PH). Single\u2010cell spatial transcriptomic analysis of PAH lungs further revealed complement\u2010rich adventitial fibroblasts, granzyme K (GZMK)\n                    <jats:sup>+<\/jats:sup>\n                    CD8 T cells, and activated macrophages forming proinflammatory niches within the pulmonary artery adventitia in the different pulmonary vascular lesions in PAH. Our recent work highlights the role of both extracellular and intracellular complement activation in fibroblast\u2010mediated pulmonary vascular inflammation. Specifically, activation of the alternative pathway within fibroblasts, through complement factors D (CFD) and B (CFB), promotes production of anaphylatoxins (C3a and C5a), cytokines, and complement\u2010containing extracellular vesicles (EVs). These mediators drive macrophage and T\u2010cell recruitment and activation, contributing to disease progression. Additionally, a fourth pathway of complement activation mediated by CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell\u2013derived GZMK, which triggers extracellular complement cascades in fibroblasts and macrophages, has recently been identified. These findings support the hypotheses that local complement production by pulmonary artery adventitial fibroblasts, activated intracellularly by CFD and CFB and extracellularly by GZMK\n                    <jats:sup>+<\/jats:sup>\n                    , and its secretion in soluble form and within EVs promotes macrophage chemotaxis and activation. These complement\u2010driven proinflammatory niches in PAH pulmonary arteries represent promising therapeutic targets in PH.\n                  <\/jats:p>","DOI":"10.1002\/cph4.70133","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:00:52Z","timestamp":1774591252000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adventitial Niches, Complement and Inflammation in Pulmonary Vascular Disease: Current Status and Future Directions"],"prefix":"10.1002","volume":"16","author":[{"given":"Hui","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Medicine Cardiovascular and Pulmonary Research Laboratroy (CVP) University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ram Raj","family":"Prasad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medicine Cardiovascular and Pulmonary Research Laboratroy (CVP) University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2290-2091","authenticated-orcid":false,"given":"Sushil","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medicine Cardiovascular and Pulmonary Research Laboratroy (CVP) University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medicine Cardiovascular and Pulmonary Research Laboratroy (CVP) University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dallas","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medicine Cardiovascular and Pulmonary Research Laboratroy (CVP) University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng\u2010Jun","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Biology University of Colorado, Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Mickael","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medicine Cardiovascular and Pulmonary Research Laboratroy (CVP) University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen\u2010Rei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medicine Cardiovascular and Pulmonary Research Laboratroy (CVP) University of Colorado Anschutz Medical Campus  Aurora Colorado 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