title: Prolylcarboxypeptidase promotes angiogenesis and vascular repair.
abstract: Prolylcarboxypeptidase (PRCP) is associated with leanness, hypertension, and thrombosis. PRCP-depleted mice have injured vessels with reduced Kruppel-like factor (KLF)2, KLF4, endothelial nitric oxide synthase (eNOS), and thrombomodulin. Does PRCP influence vessel growth, angiogenesis, and injury repair? PRCP depletion reduced endothelial cell growth, whereas transfection of hPRCP cDNA enhanced cell proliferation. Transfection of hPRCP cDNA, or an active site mutant (hPRCPmut) rescued reduced cell growth after PRCP siRNA knockdown. PRCP-depleted cells migrated less on scratch assay and murine PRCP(gt/gt) aortic segments had reduced sprouting. Matrigel plugs in PRCP(gt/gt) mice had reduced hemoglobin content and angiogenic capillaries by platelet endothelial cell adhesion molecule (PECAM) and NG2 immunohistochemistry. Skin wounds on PRCP(gt/gt) mice had delayed closure and reepithelialization with reduced PECAM staining, but increased macrophage infiltration. After limb ischemia, PRCP(gt/gt) mice also had reduced reperfusion of the femoral artery and angiogenesis. On femoral artery wire injury, PRCP(gt/gt) mice had increased neointimal formation, CD45 staining, and Ki-67 expression. Alternatively, combined PRCP(gt/gt) and MRP-14(-/-) mice were protected from wire injury with less neointimal thickening, leukocyte infiltration, and cellular proliferation. PRCP regulates cell growth, angiogenesis, and the response to vascular injury. Combined with its known roles in blood pressure and thrombosis control, PRCP is positioned as a key regulator of vascular homeostasis.
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Case WesternReserve University and University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Adams
authors.forename: Evi X
authors.initials: EX
authors.lastname: Stavrou
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
authors.forename: Alona
authors.initials: A
authors.lastname: Merkulova
authors.forename: M Amer
authors.initials: MA
authors.lastname: Alaiti
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Nakajima
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Morooka
authors.forename: Sergei
authors.initials: S
authors.lastname: Merkulov
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Larusch
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Simon
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.forename: Alvin H
authors.initials: AH
authors.lastname: Schmaier
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D017209:Apoptosis; D040502:Calgranulin B / Q000378:metabolism; D002268:Carboxypeptidases / Q000502:physiology*; D002417:Cattle; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology*; D005263:Femoral Artery / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007511:Ischemia / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D014945:Wound Healing
chemical_list: D040502:Calgranulin B; C000715467:KLF4 protein, human; D019394:Ki-67 Antigen; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase