Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke

Area of Science:

• Neuroscience
• Vascular Biology
• Biochemistry

Background:

• Tissue plasminogen activator (tPA) is a crucial thrombolytic for acute ischemic stroke but increases intra-cerebral hemorrhage (ICH) risk.
• tPA activates platelet-derived growth factor-CC (PDGF-CC) via the PDGF receptor-α (PDGFRα) on the neurovascular unit (NVU), increasing blood-brain barrier (BBB) permeability and ICH.
• The precise mechanism of PDGF-CC activation by tPA within the NVU remains unclear.

Purpose of the Study:

• To elucidate the mechanism of tPA-mediated PDGF-CC activation in the NVU.
• To investigate the role of integrin Mac-1 and endocytic receptor LRP1 in tPA-induced BBB permeability and ICH.
• To identify the cellular source responsible for early PDGF-CC activation by tPA post-stroke.

Main Methods:

• Utilized Mac-1 deficient mice (Mac-1^-/-) and wild-type littermates.
• Administered tPA and PDGF-CC via intracerebroventricular injection and middle cerebral artery occlusion (MCAO) models.
• Performed immunofluorescence staining for Mac-1, LRP1, and PDGFRα localization.
• Conducted bone-marrow transplantation studies.
• Assessed BBB permeability, ICH incidence, and infarct volume.

Main Results:

• Mac-1^-/- mice were protected from tPA-induced BBB permeability and ICH, but not from direct PDGF-CC induced permeability.
• Mac-1, LRP1, and PDGFRα were co-localized at the NVU of arterioles.
• Mac-1^-/- mice exhibited reduced PDGFRα phosphorylation, BBB permeability, and infarct volume post-MCAO.
• Resident CD11b⁺ cells, not bone-marrow-derived leukocytes, mediated early PDGF-CC activation by tPA.
• Mac-1^-/- mice were resistant to ICH even with late tPA treatment in a thrombotic stroke model.

Conclusions:

• Mac-1 and LRP1 function as essential co-factors for tPA-mediated PDGF-CC activation within the NVU.
• This interaction tightly regulates PDGFRα signaling and controls BBB permeability.
• Targeting Mac-1 and LRP1 may offer a novel strategy to mitigate ICH risk associated with tPA therapy in stroke.