Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke

Abstract

LRP1 in the NVU to promote tPA-mediated activation of PDGF-CC. Mac-1-deficient mice (Mac-1 −/−) are protected from tPA-induced BBB permeability but not from perme-ability induced by intracerebroventricular injection of active PDGF-CC. Immunofluorescence analysis demonstrates that Mac-1, LRP1, and the PDGFRα all localize to the NVU of arterioles, and following middle cerebral artery occlusion (MCAO) Mac-1 −/− mice show significantly less PDGFRα phosphorylation, BBB permeability, and infarct volume compared to wild-type mice. Bone-marrow transplantation studies indicate that resident CD11b + cells, but not bone-marrow-derived leukocytes, mediate the early activation of PDGF-CC by tPA after MCAO. Finally, using a model of thrombotic stroke with late thrombolysis, we show that wild-type mice have an increased incidence of spontaneous ICH following thrombolysis with tPA 5 h after MCAO, whereas Mac-1 −/− mice are resistant to the development of ICH even with late tPA treatment. Together, these results indicate that Mac-1 and LRP1 act as co-factors for the activation of PDGF-CC by tPA in the NVU, and suggest a novel mechanism for tightly regulating PDGFRα signaling in the NVU and controlling BBB permeability. Abstract Treatment of acute ischemic stroke with the thrombolytic tissue plasminogen activator (tPA) can significantly improve neurological outcomes; however, throm-bolytic therapy is associated with an increased risk of intra-cerebral hemorrhage (ICH). Previously, we demonstrated that during stroke tPA acting on the parenchymal side of the neurovascular unit (NVU) can increase blood-brain barrier (BBB) permeability and ICH through activation of latent platelet-derived growth factor-CC (PDGF-CC) and signaling by the PDGF receptor-α (PDGFRα). However , in vitro, activation of PDGF-CC by tPA is very inefficient and the mechanism of PDGF-CC activation in the NVU is not known. Here, we show that the integrin Mac-1, expressed on brain microglia/macrophages (denoted micro-glia throughout), acts together with the endocytic receptor Enming Joseph Su and Chunzhang Cao contributed equally to this work. Daniel A. Lawrence and Li Zhang contributed equally to this work. Electronic supplementary material The online version of this article (

Impact of Tissue Plasminogen Activator on the Neurovascular Unit: From Clinical Data to Experimental Evidence

“…Altogether, these events were associated with detachment of astrocytic end-feet from the basal lamina and subsequent increased BBB permeability (Polavarapu et al, 2007). In addition, it has been reported that rtPA could mediate the local activation of latent platelet-derived growth factor-CC (PDGF-CC) and subsequent activation of PDGF-a receptors on pericytes after cerebral ischemia (Macrez et al, 2011a, b), an effect leading to hemorrhagic transformation (Su et al, 2008). Indeed, intraventricular injection of rtPA or active PDGF-CC, in the absence of ischemia, led to significant increase in BBB permeability.…”

Protein microarray analysis identifies key cytokines associated with malignant middle cerebral artery infarction

“…PDGFA is observed to be involved in atherosclerotic stroke previously (Xu et al, 2008). PDGF signaling is also reported to regulate blood-brain barrier permeability and integrity during ischemic stroke (Su et al, 2008). EGF has been shown to be implicated in neurogenesis and neuroprotection.…”

Osteoblasts Have a Neural Origin in Heterotopic Ossification

“…Both PDGFRa, a factor associated with perivascular astrocytes [38] and shown to be involved in glial-endothelial cell interactions and critical for maintenance of the BBB [38], and musashi, which is an RNA-binding protein that is highly specific for neural stem cells [23] and is not expressed in fully differentiated cells [26], were assessed in the claudin 5 + cells. FACS analysis showed that PDGFRa was expressed on these cells (Fig.…”