RNA therapeutics
High Lp(a) impairs new blood vessel growth after limb ischemia, but a growth-factor gene therapy restores it in mice (Circulation 2002)
Original title: Impairment of collateral formation in lipoprotein(a) transgenic mice: therapeutic angiogenesis induced by human hepatocyte growth factor gene
This study examined whether Lp(a) impairs collateral blood vessel formation in a mouse model of peripheral arterial disease, and tested gene therapy with hepatocyte growth factor (HGF) as a treatment. Lp(a) transgenic mice showed significantly less natural blood flow recovery after arterial occlusion than non-transgenic mice, with a significant negative correlation between serum Lp(a) and blood flow recovery (P<0.05); Lp(a) also stimulated vascular smooth muscle growth via ERK phosphorylation. Intramuscular injection of HGF plasmid significantly increased blood flow even in Lp(a) transgenic mice, alongside detectable human HGF protein and significantly increased capillary density compared with controls (P<0.01). The findings show high Lp(a) impairs collateral vessel formation after limb ischemia, but HGF gene therapy can induce therapeutic angiogenesis despite elevated Lp(a), suggesting a potential treatment approach for peripheral arterial disease.
Original 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 (P<0.05). 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. Intramuscular injection of HGF plasmid resulted in a significant increase in blood flow even in Lp(a) transgenic mice, accompanied by the detection of human HGF protein. A significant increase in capillary density also was detected in Lp(a) transgenic mice transfected with human HGF compared with control (P<0.01).
Conclusions: Overall, a high serum Lp(a) concentration impaired collateral formation. Although the delay of angiogenesis in high serum Lp(a) might diminish angiogenesis, intramuscular injection of HGF plasmid induced therapeutic angiogenesis in the Lp(a) transgenic ischemic hindlimb mouse model as potential therapy for PAD.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.