Endothelial Targets in Stroke: Translating Animal Models to Human

Abstract

Cerebral ischemia (stroke) induces injury to the cerebral endothelium that may contribute to parenchymal injury and worsen outcome. This review focuses on current preclinical studies examining how to prevent ischemia-induced endothelial dysfunction. It particularly focuses on targets at the endothelium itself. Those include endothelial tight junctions, transcytosis, endothelial cell death, and adhesion molecule expression. It also examines how such studies are being translated to the clinic, especially as adjunct therapies for preventing intracerebral hemorrhage during reperfusion of the ischemic brain. Identification of endothelial targets may prove valuable in a search for combination therapies that would specifically protect different cell types in ischemia.

Keywords: blood-brain barrier; permeability; reperfusion; tight junctions; transcytosis.

Figure 1.

Schematic of the role of stroke-induced endothelial dysfunction in brain injury.

Figure 2.

Preclinical studies have indicated that inflammation, free radicals and NVU PDGF signaling are involved in the BBB hyperpermeability and cerebral hemorrhage that can accompany t-PA induced reperfusion for cerebral ischemia. This has led to clinical trials examining inhibitors of these pathways as adjunct therapies for tPA-induced reperfusion (fingolimod/inflammation, edaravone/free radicals and imatinib/PDGF signaling). In addition, a mutant form of APC, 3K3A-APC, is being tested as an adjunct therapy. It has pleiotropic effects including being vasculoprotective via protease activated receptor (PAR)-1/Akt signaling.