Perlecan is essential for the functioning and repair of the blood-brain barrier through interacting with and activating pericytes in a mouse ischemic stroke model

Authors

• K Nakamura
• T Ikeuchi
• P Zhang
• C Rhodes
• Y Chiba
• Y Mukouyama
• Y Yamada

Abstract

Ischemic stroke with severe symptoms is the leading cause of disability. Disruption of the blood-brain barrier (BBB), a highly selective permeability barrier, occurs when the integrity of BBB components is lost under the ischemic conditions. In the process of repairing the BBB function, pericytes are activated by platelet-derived growth factor receptor ß (PDGFRß). Perlecan, a major heparan sulfate proteoglycan of the basement membrane, is expressed by brain endothelial cells (ECs), adjacent to pericytes. We hypothesized that perlecan may play a protective role in the BBB maintenance and may regulate pericyte activation. We induced middle cerebral artery occlusion (MCAO) for 60 minutes in adult conditional perlecan-deficient (Perlecan KO-Tg) mice, which express the perlecan transgene only in the cartilage to rescue the lethality of Perlecan KO mice. Perlecan KO-Tg mice demonstrated larger infarct volumes and more BBB leakage than the control mice after MCAO. Perlecan KO-Tg mice had decreased numbers of PDGFRß-positive pericytes in the ischemic lesion compared to control mice. In wild-type mice, the expression of both perlecan and integrin a5, a potential receptor for perlecan, was upregulated in the ischemic lesion. In addition, cultured pericytes attached to recombinant perlecan domain V (DV) through integrin a5ß1, and DV promoted the PDGF-induced migration of pericytes. These results revealed that the interaction between perlecan and pericytes is important for the maintenance and also for the repair process of the BBB after ischemic stroke. Perlecan DV may be useful as a potential therapeutic agent promoting repair of the BBB function in ischemic stroke.

Scientific Focus Area: Cell Biology

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