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

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.