Beneficial effects of concurrent autologous bone marrow cell therapy and metabolic intervention in ischemia-induced angiogenesis in the mouse hindlimb.
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.
Napoli
Claudio
C
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
Williams-Ignarro
Sharon
S
de Nigris
Filomena
F
de Rosa
Gaetano
G
Lerman
Lilach O
LO
Farzati
Bartolomeo
B
Matarazzo
Angelo
A
Sica
Giacomo
G
Botti
Chiara
C
Fiore
Andrea
A
Byrns
Russell E
RE
Sumi
Daigo
D
Sica
Vincenzo
V
Ignarro
Louis J
LJ
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
D000975:Antioxidants; D009566:Nitrates; D009573:Nitrites; D001120:Arginine