Proposed model for t-PA/Plgn–mediated, receptor-dependent BBB modulation via the Rho/ROCK pathway. t-PA binds an astrocytic cell surface receptor, possibly LRP-1, via its kringle 1, EGF, or Finger domains (or their combination). The t-PA receptor colocalizes on the cell surface with a Plgn binding receptor (or protein) that uses exposed lysines to bind the Plgn kringles. This receptor-mediated colocalization of t-PA and Plgn provides the “cofactor” requires for effective t-PA–induced plasmin (Pln) generation at specific locations on the astrocyte surface. Plasmin in turn activates a yet-to-be identified target protein, triggering key signaling pathways in the astrocyte (ie, the MAPK, PI3 kinase, and Rho/ ROCK pathways). ROCK activation leads to substantial cytoskeletal changes in the astrocyte, resulting in astrocyte retraction that compromises the BBB structure and increases its permeability. Other plasminogen activators (PAs), such as u-PA, cannot use the same t-PA receptors. Pln activation by these PAs occurs in the extracellular fluid or in other areas on the cell surface that cannot participate in similar signal-transducing events, rendering these PAs ineffective as BBB modulators.