Impairment of Collateral Formation in Lipoprotein(a) Transgenic Mice

Abstract

Background-Although lipoprotein(a) (Lp[a]) is a risk factor for atherosclerosis, no study has documented the effects of Lp(a) on angiogenesis. In this study, we examined collateral formation in peripheral arterial disease (PAD) model in Lp(a) transgenic mice. In addition, we examined the feasibility of gene therapy by using an angiogenic growth factor, hepatocyte growth factor (HGF), to treat PAD in the presence of high Lp(a). Methods and Results-In Lp(a) transgenic mice, the degree of natural recovery of blood flow after operation was significantly lower than that in nontransgenic mice. Of importance, there was a significant negative correlation between serum Lp(a) concentration and the degree of natural recovery of blood flow (PϽ0.05). In addition, Lp(a) significantly stimulated the growth of vascular smooth muscle, accompanied by the phosphorylation of ERK. These data demonstrated the association of impairment of collateral formation with serum Lp(a) concentration. Thus, we examined the feasibility of therapeutic angiogenesis by using HGF, with the goal of progression to human gene therapy. In a large proportion of these patients, the anatomic extent and the distribution of arterial occlusive disease make the patients unsuitable for operative or percutaneous revascularization. Thus, the disease frequently follows an inexorable downhill course. 2,3 One of the risk factors related to peripheral arterial disease is a high concentration of serum lipoprotein(a) (Lp[a]) because Lp(a) is also a risk factor for atherosclerosis, restenosis after angioplasty, ischemic heart disease, and cerebral stroke. 4 -9 Lp(a) consists of LDL with an additional protein component, apolipoprotein (a) (apo [a]), a homologue of plasminogen. 10 Lp(a) and apo(a) have been thought to enhance proliferation of human vascular smooth muscle cells (VSMCs). [11][12][13][14] On the other hand, Lp(a) has been postulated to bind to endothelial cells and macrophages and to extracellular components such as fibrin and inhibit cell-associated plasminogen activation. 15,16 Moreover, the inhibition of activation of transforming growth factor (TGF)-␤ by Lp(a) because of its strong homology to plasminogen has been reported. 11 Because TGF-␤ is also known to have proangiogenic properties, Lp(a) might inhibit angiogenesis from this aspect. In contrast, there is less evidence for the stimulation of Lp(a) on angiogenesis, although the proliferation of VSMCs might promote collateral formation in the case that endothelial cells would be stimulated by Lp(a). Nevertheless, no [17][18][19][20] Thus, a strategy for therapeutic angiogenesis with the use of angiogenic growth factors should be considered for the treatment of patients with critical limb ischemia or myocardial infarction. In addition to VEGF, we and others have reported the angiogenic property of hepatocyte growth factor (HGF) in a rabbit ischemia model. [21][22][23][24] Thus, it is preferable to stimulate angiogenesis by HGF, not only in a normal model but also in other high-risk conditions such as ...

Hepatocyte growth factor secreted by cultured adipocytes promotes tube formation of vascular endothelial cells in vitro

“…Human recombinant HGF has been applied in therapeutic angiogenesis, as a cytokine supplement for patients with arteriosclerosis obliterans. 29 Hepatocyte growth factor is also seen as a significant cardioprotective factor because of its potent angiogenetic properties 14,30 and because HGF can reduce restenosis after balloon injury by enhancing re-endothelialization. 31 On the other hand, plasma HGF levels are elevated in malignancies, 32 patients with atherosclerosis and proliferative diabetic retinopathy.…”

“…Hepatocyte growth factor (HGF) is another endothelial growth factor with potent angiogenetic and mitogenic effects. 13,14 Recently, HGF as well as VEGF are being used in 'therapeutic angiogenesis'. 15,16 Serum HGF levels are elevated not only in patients with hepatic desease.…”

Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia

“…4 In various animal models, transfection of naked plasmid DNA encoding the human HGF gene has achieved effective angiogenesis. [5][6][7][8][9][10][11] The first human clinical trial of HGF gene therapy for PAD was performed in Japan, and showed that intramuscular injection of naked HGF plasmid was well tolerated. 12 A subsequent multicenter, randomized, double-blind, dose-finding, placebo-controlled, trial performed in the USA showed that an injection of the HGF gene increased the tissue perfusion compared with placebo.…”

Effect of exogenous adipose-derived stem cells in the early stages following free fat transplantation

“…VEGF and bFGF are considered to mobilize and recruit endothelial (progenitor) cells, subsequently accelerating the onset of angiogenesis (7). HGF is an additional important endothelial growth factor with potential angiogenic and mitogenic effects (8). Cotransplantation of ASCs with aspirated fat tissue may improve graft retention due to angiogenic effects.…”