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Emerging evidence suggests a direct role of localized PCSK9 in the pathogenesis of vascular diseases. With this in our consideration, we reviewed PCSK9 physiology with respect to recent development and major studies (clinical and experimental) on PCSK9 functionality in vascular disease. PCSK9 upregulates low\u2010density lipoprotein (LDL)\u2010cholesterol levels by binding to the LDL\u2010receptor (LDLR) and facilitating its lysosomal degradation.\n                    <jats:italic>PCSK9<\/jats:italic>\n                    gain\u2010of\u2010function mutations have been confirmed as a novel genetic mechanism for familial hypercholesterolemia. Elevated serum PCSK9 levels in patients with vascular diseases may contribute to coronary artery disease, atherosclerosis, cerebrovascular diseases, vasculitis, aortic diseases, and arterial aging pathogenesis. Experimental models of atherosclerosis, arterial aneurysm, and coronary or carotid artery ligation also support PCSK9 contribution to inflammatory response and disease progression, through LDLR\u2010dependent or \u2010independent mechanisms. More recently, several clinical trials have confirmed that anti\u2010PCSK9 monoclonal antibodies can reduce systemic LDL levels, total nonfatal cardiovascular events, and all\u2010cause mortality. Interaction of PCSK9 with other receptor proteins (LDLR\u2010related proteins, cluster of differentiation family members, epithelial Na\n                    <jats:sup>+<\/jats:sup>\n                    channels, and sortilin) may underlie its roles in vascular disease. Improved understanding of PCSK9 roles and molecular mechanisms in various vascular diseases will facilitate advances in lipid\u2010lowering therapy and disease prevention.\n                  <\/jats:p>","DOI":"10.1002\/jcp.30025","type":"journal-article","created":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T01:34:55Z","timestamp":1599010495000},"page":"2333-2351","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Physiology and role of PCSK9 in vascular disease: Potential impact of localized PCSK9 in vascular wall"],"prefix":"10.1002","volume":"236","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1070-7774","authenticated-orcid":false,"given":"Yanan","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Cardiology The Second Xiangya Hospital of Central South University  Changsha China"},{"name":"Department of Biochemistry &amp; Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine The University of Calgary  Calgary Alberta Canada"},{"name":"Department of Physiology &amp; Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine The University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binjie","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine The University of Calgary  Calgary Alberta Canada"},{"name":"Department of Physiology &amp; Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine The University of Calgary  Calgary Alberta Canada"},{"name":"Department of Pathophysiology, Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province University of South China  Hengyang Hunan 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