Therapeutic effects of autologous bone marrow cells and metabolic intervention in the ischemic hindlimb of spontaneously hypertensive rats involve reduced cell senescence and CXCR4/Akt/eNOS pathways

J Cardiovasc Pharmacol. 2007 Oct;50(4):424-33. doi: 10.1097/FJC.0b013e31812564e4.

Abstract

Peripheral arterial disease (PAD) is a major health problem, especially when associated with severe hypertension. Administration of autologous bone marrow cells (BMCs) is emerging as a novel intervention to induce neoangiogenesis in ischemic limb models and in patients with PAD. This study evaluates the neovascularization capacity of BMCs alone or in combination with metabolic cotreatment (0.8% vitamin E, 0.05% vitamin C, and 5% of L-arginine) in a rat model of ischemic hindlimbs of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Molecular mechanisms were investigated in bone marrow-derived endothelial progenitor cells (BM-EPC) derived from rats. BMC therapy increased blood flow and capillary densities and Ki67 proliferative marker, and it decreased interstitial fibrosis. These effects were amplified by metabolic cotreatment, an intervention that induces vascular protection at least partly through the nitric oxide (NO)/endothelial nitric oxide synthase (eNOS) pathway, reduction of systemic oxidative stress, and macrophage activation. In addition, BMC therapy alone and, more consistently, in combination with metabolic treatment, ameliorated BM-EPC functional activity via decreased cellular senescence and improved homing capacity by increasing CXCR4-expression levels. These data suggest potential therapeutic effects of autologous BMCs and metabolic treatment in hypertensive PAD patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / therapeutic use
  • Apoptosis / drug effects
  • Arginine / therapeutic use
  • Arteries / drug effects
  • Arteries / metabolism
  • Arteries / physiopathology
  • Bone Marrow Transplantation / methods*
  • Capillaries / pathology
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Hindlimb / blood supply*
  • Hindlimb / drug effects
  • Hindlimb / physiopathology
  • Ischemia / metabolism
  • Ischemia / physiopathology
  • Ischemia / therapy*
  • Leukocytes / pathology
  • Male
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • Muscle, Skeletal / blood supply
  • Muscle, Skeletal / pathology
  • Nitric Oxide / blood
  • Nitric Oxide Synthase Type II / metabolism
  • Nitric Oxide Synthase Type III
  • Oxidative Stress / drug effects
  • Peripheral Vascular Diseases / therapy
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Receptors, CXCR4 / metabolism
  • Regional Blood Flow

Substances

  • Antioxidants
  • Cxcr4 protein, rat
  • Receptors, CXCR4
  • Nitric Oxide
  • Arginine
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Proto-Oncogene Proteins c-akt