title: Beneficial effects of concurrent autologous bone marrow cell therapy and metabolic intervention in ischemia-induced angiogenesis in the mouse hindlimb.
abstract: Lower-limb ischemia is a major health problem. Because of the absence of effective treatment in the advanced stages of the disease, amputation is undertaken to alleviate unbearable symptoms. Novel therapeutic approaches include the intramuscular use of autologous bone marrow cells (BMCs). Because tissue ischemia is associated with an overwhelming generation of oxygen radicals and negative effects due to perturbed shear-stress, metabolic intervention with antioxidants and l-arginine could potentially induce beneficial effects beyond those achieved by BMCs. The protective effect of autologous BMCs and vascular protection by metabolic cotreatment (1.0% vitamin E added to the chow and 0.05% vitamin C and 6% l-arginine added to the drinking water) were examined in ischemia-induced angiogenesis in the mouse hindlimb, a model of extensive acute peripheral arterial occlusion. i.v. BMC therapy improved blood flow and increased capillary densities and expression of Ki-67, a proliferation-associated protein. This beneficial effect was amplified by metabolic cotreatment, an intervention inducing vascular protection, at least in part, through the nitric oxide pathway, reduction of systemic oxidative stress, and macrophage activation. Therefore, although a cautious approach is mandatory when experimental findings are extended to human diseases, autologous BMCs together with metabolic intervention could be an effective clinical treatment for peripheral arterial disease.
authors.affiliation: Department of General Pathology, Division of Clinical Pathology and Excellence Research Center on Cardiovascular Diseases, School of Medicine, Second University of Naples, Naples 80138, Italy. claunap@tin.it
authors.forename: Claudio
authors.initials: C
authors.lastname: Napoli
authors.forename: Sharon
authors.initials: S
authors.lastname: Williams-Ignarro
authors.forename: Filomena
authors.initials: F
authors.lastname: de Nigris
authors.forename: Gaetano
authors.initials: G
authors.lastname: de Rosa
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.forename: Bartolomeo
authors.initials: B
authors.lastname: Farzati
authors.forename: Angelo
authors.initials: A
authors.lastname: Matarazzo
authors.forename: Giacomo
authors.initials: G
authors.lastname: Sica
authors.forename: Chiara
authors.initials: C
authors.lastname: Botti
authors.forename: Andrea
authors.initials: A
authors.lastname: Fiore
authors.forename: Russell E
authors.initials: RE
authors.lastname: Byrns
authors.forename: Daigo
authors.initials: D
authors.lastname: Sumi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Sica
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001120:Arginine / Q000008:administration & dosage; D016026:Bone Marrow Transplantation / Q000473:pathology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects; D014182:Transplantation, Autologous / Q000473:pathology
chemical_list: D000975:Antioxidants; D009566:Nitrates; D009573:Nitrites; D001120:Arginine