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. Author manuscript; available in PMC: 2019 May 15.
Published in final edited form as: Neuropharmacology. 2017 Sep 18;134(Pt B):293–301. doi: 10.1016/j.neuropharm.2017.09.021

Figure 1.

Figure 1

The Protein C (PC) pathway and the protective effects of activated protein C (APC) after ischemic injury. There are four major PC pathways. 1. PC activation. PC, bound to its receptor, endothelial protein C receptor (EPCR), is activated by thrombomodulin (TM)-bound thrombin (IIa) complex on the endothelial cell surface. 2. Antithrombotic activity. APC employs its anticoagulant activities by proteolytic inactivation of factor Va (FVa) and factor VIIIa (FVIIIa) aided by the cofactor Protein S (PS). 3. Cytoprotective signaling. APC associated with EPCR cleaves protease-activated receptor-1 (PAR-1) in caveolae initiating cytoprotective signaling including altered gene expression, and anti-inflammatory, anti-apoptotic and barrier protective activities. Other receptors (not shown) may also contribute to cytoprotective signaling. 4. APC is inhibited by serine protease inhibitors (Serpins). APC is transported across the blood-brain barrier (BBB) into brain where it has many protective and regenerative effects. APC treatment after ischemic stroke limits brain injuries by protecting the BBB and neurons and reducing inflammatory responses. Furthermore, APC promotes neovascularization and neurogenesis, and it improves neural stem cell (NSC) proliferation, integration and neurogenic activity, aiding functional recovery.