Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1-and CXCL1-mediated macrophage infiltration

• Type of Material: Article
• Authors: Ebony Washington Remus, Emory University; Iqbal Sayeed, Emory University; Soonmi Won, Emory University; Alicia Lyle, Emory University; Donald Stein, Emory University
• Language: English
• Date: 2015-09-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.expneurol.2015.07.010
• Title of Journal or Parent Work: Experimental Neurology
• ISSN: 0014-4886
• Volume: 271
• Start Page: 401
• End Page: 408
• Grant/Funding Information: Partial funding for some of the assays used in this project was provided by BHR Pharma and the Marcus Foundation.; This work was supported by NIH UO1 NS062676 to DGS and AHA SDG grant 11SDG5430002 to IS.
• Keywords: Endothelial cells; EXPRESSION; CEREBRAL-ARTERY OCCLUSION; ISCHEMIC-STROKE; BLOOD-BRAIN-BARRIER; MYOCARDIAL-INFARCTION; RATS; ISCHEMIA/REPERFUSION INJURY; Brain ischemia; Neurosciences & Neurology; Neurosciences; Life Sciences & Biomedicine; Science & Technology; Cerebrovascular repair; Macrophage infiltration; Progesterone; ANGIOGENESIS
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery; Biology, Neuroscience

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 1. h 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.