Thrombopoietin gene transfer-mediated enhancement of angiogenic responses to acute ischemia. Academic Article uri icon

Overview

MeSH

  • Acute Disease
  • Adenoviridae
  • Animals
  • Antigens, CD31
  • Blood Platelets
  • Cell Differentiation
  • Gene Transfer, Horizontal
  • Hindlimb
  • Megakaryocytes
  • Mice
  • Mice, Inbred C57BL
  • Platelet Count
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1

MeSH Major

  • Genetic Therapy
  • Ischemia
  • Neovascularization, Physiologic
  • Thrombopoietin

abstract

  • The development of new blood vessels is a complex process, likely requiring the synergy of multiple angiogenic mediators. This study focuses on the proximal angiogenic response using the platelet as a complex carrier of critical mediators of angiogenesis. Platelet levels are controlled by circulating levels of thrombopoietin (TPO) functioning to activate megakaryocyte differentiation and platelet release through the c-mpl receptor. We hypothesized that TPO gene transfer should enhance correction of experimental ischemia by providing increased levels of platelets and hence platelet-derived mediators of angiogenesis. To evaluate this hypothesis, we dissected the role of the TPO-c-mpl-megakaryocyte-platelet pathway in the angiogenic response using a model of acute hindlimb ischemia of wild-type, TPO(-/-), and c-mpl(-/-) mice. The data demonstrate that infusion of platelets will enhance the angiogenic response in wild-type mice and that the endogenous angiogenic response is blunted in TPO(-/-) and c-mpl(-/-) mice. Consistent with this observation, adenovirus (Ad)-mediated transfer of TPO (AdTPO) enhanced the correction of ischemia in wild-type and TPO(-/-), but not c-mpl(-/-), mice. Local versus systemic administration of AdTPO showed that the effect of TPO gene transfer was systemic, not local, and it could be replaced by gene transfer of VEGF, one of the many mediators of angiogenesis carried by the platelets, even in the absence of components in the TPO-c-mpl-megakaryocyte-platelet pathway.

publication date

  • August 19, 2005

has subject area

  • Acute Disease
  • Adenoviridae
  • Animals
  • Antigens, CD31
  • Blood Platelets
  • Cell Differentiation
  • Gene Transfer, Horizontal
  • Genetic Therapy
  • Hindlimb
  • Ischemia
  • Megakaryocytes
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic
  • Platelet Count
  • Thrombopoietin
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1161/01.RES.0000179534.17668.f8

PubMed ID

  • 16051888

Additional Document Info

start page

  • 337

end page

  • 345

volume

  • 97

number

  • 4