Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia

Circulation. 2001 Jan 2;103(1):125-32. doi: 10.1161/01.cir.103.1.125.

Abstract

Background: Human tissue kallikrein (HK) releases kinins from kininogen. We investigated whether adenovirus-mediated HK gene delivery is angiogenic in the context of ischemia.

Methods and results: Hindlimb ischemia, caused by femoral artery excision, increased muscular capillary density (P:<0.001) and induced the expression of kinin B(1) receptor gene (P:<0.05). Pharmacological blockade of B(1) receptors blunted ischemia-induced angiogenesis (P:<0.01), whereas kinin B(2) receptor antagonism was ineffective. Intramuscular delivery of adenovirus containing the HK gene (Ad. CMV-cHK) enhanced the increase in capillary density caused by ischemia (969+/-32 versus 541+/-18 capillaries/mm(2) for control, P:<0.001), accelerated blood flow recovery (P:<0.01), and preserved energetic charge of ischemic muscle (P:<0.01). Chronic blockade of kinin B(1) or B(2) receptors prevented HK-induced angiogenesis.

Conclusions: HK gene delivery enhances the native angiogenic response to ischemia. Angiogenesis gene therapy with HK might be applicable to peripheral occlusive vascular disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Bradykinin Receptor Antagonists
  • Capillaries / cytology
  • Capillaries / drug effects
  • Capillaries / metabolism
  • Disease Models, Animal
  • Gene Expression
  • Genetic Therapy / methods*
  • Hindlimb / blood supply*
  • Hindlimb / drug effects
  • Humans
  • Immunohistochemistry
  • Injections, Intramuscular
  • Ischemia / genetics
  • Ischemia / pathology
  • Ischemia / therapy*
  • Male
  • Mice
  • Muscle, Skeletal / blood supply
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Neovascularization, Physiologic / drug effects*
  • Neovascularization, Physiologic / genetics
  • Peripheral Vascular Diseases / therapy
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin / metabolism
  • Regional Blood Flow / drug effects
  • Regional Blood Flow / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Kallikreins / administration & dosage*
  • Tissue Kallikreins / genetics
  • Transgenes / genetics

Substances

  • Bradykinin Receptor Antagonists
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin
  • Tissue Kallikreins