title: Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1- and CXCL1-mediated macrophage infiltration.
abstract: The neuroprotective effects of progesterone after ischemic stroke have been established, but the role of progesterone in promoting cerebrovascular repair remains under-explored. Male Sprague-Dawley rats underwent transient middle cerebral artery occlusion (tMCAO) for 90 min followed by reperfusion for 3 days. Progesterone (8 mg/kg/day) was administered intraperitoneally at 1h after initial occlusion followed by subcutaneous injections at 6, 24 and 48 h post-occlusion. Rats were euthanized after 72 h and brain endothelial cell density and macrophage infiltration were evaluated within the cerebral cortex. We also assessed progesterone's ability to induce macrophage migration toward hypoxic/reoxygenated cultured endothelial cells. We found that progesterone treatment post-tMCAO protects ischemic endothelial cells from macrophage infiltration. We further demonstrate that infiltration of monocytes/macrophages can be induced by potent chemotactic factors such as monocyte chemoattractant protein-1 (MCP-1) and the chemokine ligand 1 (CXCL1), secreted by hypoxic/reoxygenated endothelial cells. Progesterone blunts secretion of MCP-1 and CXCL1 from endothelial cells after hypoxia/reoxygenation injury and decreases leukocyte infiltration. The treatment protects ischemic endothelial cells from macrophage infiltration and thus preserves vascularization after ischemic injury.
authors.affiliation: Department of Emergency Medicine Brain Research Laboratory, Emory University, Atlanta, GA, USA.
authors.forename: Ebony Washington
authors.initials: EW
authors.lastname: Remus
authors.affiliation: Department of Emergency Medicine Brain Research Laboratory, Emory University, Atlanta, GA, USA.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
authors.affiliation: Department of Emergency Medicine Brain Research Laboratory, Emory University, Atlanta, GA, USA.
authors.forename: Soonmi
authors.initials: S
authors.lastname: Won
authors.affiliation: Department of Cardiology, Emory University Atlanta, GA, USA.
authors.forename: Alicia N
authors.initials: AN
authors.lastname: Lyle
authors.affiliation: Department of Emergency Medicine Brain Research Laboratory, Emory University, Atlanta, GA, USA. Electronic address: dstei04@emory.edu.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D054360:Chemokine CXCL1 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D011374:Progesterone / Q000627:therapeutic use*; D011372:Progestins / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D016207:Cytokines; D019394:Ki-67 Antigen; D011374:Progesterone; D011372:Progestins; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C491766:Ccl2 protein, rat; C513297:Cxcl1 protein, rat
keywords: Brain ischemia; Cerebrovascular repair; Endothelial cells; Macrophage infiltration; Progesterone