Therapeutically Targeting Platelet-Derived Growth Factor-Mediated Signaling Underlying the Pathogenesis of Subarachnoid Hemorrhage-Related Vasospasm

Michael George Zaki Ghali, Visish M. Srinivasan, Jeremiah Johnson, Peter Kan, Gavin Britz

Research output: Contribution to journalReview article

Abstract

Introduction: Vasospasm accounts for a large fraction of the morbidity and mortality burden in patients sustaining subarachnoid hemorrhage (SAH). Platelet-derived growth factor (PDGF)-β levels rise following SAH and correlate with incidence and severity of vasospasm. Methods: The literature was reviewed for studies investigating the role of PDGF in the pathogenesis of SAH-related vasospasm and efficacy of pharmacological interventions targeting the PDGF pathway in ameliorating the same and improving clinical outcomes. Results: Release of blood under high pressure into the subarachnoid space activates the complement cascade, which results in release of PDGF. Abluminal contact of blood with cerebral vessels increases their contractile response to PDGF-β and thrombin, with the latter upregulating PDGF-β receptors and augmenting effects of PDGF-β. PDGF-β figures prominently in the early and late phases of post-SAH vasospasm. PDGF-β binding to the PDGF receptor-β results in receptor tyrosine kinase domain activation and consequent stimulation of intracellular signaling pathways, including p38 mitogen-activated protein kinase, phosphatidylinositol-3-kinase, Rho-associated protein kinase, and extracellular regulated kinase 1 and 2. Consequent increases in intracellular calcium and increased expression of genes mediating cellular growth and proliferation mediate PDGF-induced augmentation of vascular smooth muscle cell contractility, hypertrophy, and proliferation. Conclusion: Treatments with statins, serine protease inhibitors, and small molecular pathway inhibitors have demonstrated varying degrees of efficacy in prevention of cerebral vasospasm, which is improved with earlier institution.

Original languageEnglish (US)
Pages (from-to)2289-2295
Number of pages7
JournalJournal of Stroke and Cerebrovascular Diseases
Volume27
Issue number9
DOIs
StatePublished - Sep 2018
Externally publishedYes

Keywords

  • complement
  • MAPK
  • nafamostat mesylate
  • platelet-derived growth factor
  • ROCK
  • statins
  • subarachnoid hemorrhage
  • Vasospasm

ASJC Scopus subject areas

  • Surgery
  • Rehabilitation
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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