Platelet-Derived PDGF-A Disrupts Blood-Brain Barrier Integrity in Ischemic Stroke-Brief Report

Abstract

Background: Ischemic stroke (IS) is a prevalent cause of death and disability worldwide. Cerebral ischemia induces profound changes at the blood-brain barrier, which lead to a remarkable increase in paracellular permeability, worsening outcomes. Platelets are well known for safeguarding vascular integrity and the prevention of bleeding complications. On the other hand, platelet activation contributes to infarct progression in the context of IS. The manifold, context-dependent roles of platelets, however, have not yet been resolved.

Methods: IS was mimicked by transient middle cerebral artery occlusion in wild-type, transgenic, or treated mice, and vascular leakage was assessed by intravital 2-photon microscopy, as well as Western blotting and immunohistochemistry. Barrier property of primary murine brain microvascular endothelial cells was measured as transendothelial electrical resistance of cellular monolayers in response to platelet releasate or recombinant proteins.

Results: IS induces blood-brain barrier breakdown characterized by time-dependent leakage of albumin in the brain parenchyma. We could show that local platelet activation triggers the release of PDGF (platelet-derived growth factor)-A from α-granules, which induces the loss of brain endothelial cell layer integrity. This translates to a comprised vascular integrity in vivo. In the absence of α-granule content (Nbeal2^-/-) or pharmacological blockade of PDGF, no disruption of the endothelial layer or vascular leakage was observed.

Conclusions: PDGF-A released from platelets impairs blood-brain barrier integrity, resulting in detrimental vascular leakage and infarct progression. These findings provide important insights on the pivotal role of platelets in IS further elucidating the mechanisms of thrombo-inflammation in the brain.

Keywords: blood platelets; blood-brain barrier; platelet-derived growth factor; stroke; thrombo-inflammation.