TPA and proteolysis in the neurovascular unit.

Abstract

One of the major recommendations emerging from the NINDS Stroke Progress Review Group was to shift the emphasis from a purely neurocentric view of cell death toward a more integrative approach whereby responses in all brain cells and matrix are considered during cerebral ischemia (see Figure). The concept of the neurovascular unit (fundamentally comprising endothelium, astrocyte, and neuron) provides a modular framework where cell-cell signaling and cell-matrix interactions mediate the overall tissue response to stroke and its treatments.1 There is no doubt that reperfusing blood vessels mechanically or pharmacologically prevents cell death and rescues brain when performed in a timely manner, as it does in ischemic myocardium. However, under some circumstances, thrombolysis and reperfusion lead to cerebral hemorrhage and edema. Here, we examine the hypothesis that beneficial versus potentially deleterious outcomes after tissue plasminogen activator (tPA) stroke therapy may relate in part to matrix proteolysis within the neurovascular unit, and review recent advances in this area. Schematic of the basic neurovascular unit showing functional interactions between neuron, astrocyte, and cerebral endothelium. This conceptual construct provides a framework for investigating the integrative response of brain to stroke and therapy. Note: ultimately, all cell types should be considered including smooth muscle cells, pericytes, as well as oligodendrocytes and axons in white matter. More than 7 years after the major ECASS and NINDS trials,2,3 use of tPA therapy remains limited.4 In part, this may be due to narrow time-to-treatment windows and apparent complications …