Estrogen Stimulates Angiogenesis in Normoperfused Skeletal Muscle in Rabbits
Histological analysis performed at the day 30 in the ischemic and the nonischemic hindlimbs demonstrated that in the ischemic hindlimb, the capillary/muscle fiber was increased in the treated groups. In the nonischemic hindlimb, the capillary/muscle fiber was 0.81±0.04 in the placebo group, 0.97±0.14 in Group 1, 0.93±0.16 in Group 2, and 1.04±0.07 in Group 3 (P<0.05 versus placebo), (F=4.53, P=0.01). The capillary/muscle fiber of the nonischemic hindlimb was related to that of the ischemic hindlimb (P<0.0001, r=0.88) and to the 17-β estradiol blood levels of day 30 (P<0.01, r=0.54).
This is the first time that the development of neovascularization has been demonstrated in a remote normoperfused limb after administration of a growth factor such as estrogen.
- Copyright © 2001 by American Heart Association
Gowdak LHW, Poliakova L, Wang X, et al. Adenovirus-mediated VEGF121 gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia. Circulation. 2000;102:565–571.
Kyriakides ZS, Petinakis P, Kaklamanis L, et al. Intramuscular administration of estrogen may promote angiogenesis and perfusion in a rabbit model of chronic limb ischemia. Cardiovasc Res. 2001;49:626–633.
In their letter, Kyriakìdes et al describe their recent results showing that intramuscular administration of estrogens to ischemic limb skeletal muscle promotes angiogenesis, not only at the site of injection, but also in the nonischemic contralateral limb. Their results add to the evidence that neovascularization can be induced in normoperfused tissues.
In the past decade, it has been well established in animal studies that treatment with angiogenic growth factors can induce angiogenesis in ischemic tissues, thus improving tissue perfusion. However, chronic tissue ischemia has been regarded as an essential precondition for the induction of angiogenesis, and it was questioned whether neovascularization could be induced in normoperfused tissues.R1 This issue is highly relevant clinically because the majority of patients with coronary artery disease or peripheral artery disease do not have sustained chronic ischemia; rather, they have normal resting blood flow with occasional episodes of acute ischemia, frequently induced by physical exercise. Thus, if chronic ischemia were necessary for angiogenic growth factors to induce development of new blood vessels, most patients with coronary artery disease or peripheral vascular disease would not be candidates for treatment with angiogenic growth factors.
The results of Kyriakìdes et al are in agreement with other studies. In a variety of in vivo angiogenesis assays, commonly used to study positive and negative regulators of angiogenesis,R2 it is not necessary to induce ischemia or hypoxia in order to demonstrate the angiogenic properties of positive regulators of angiogenesis.
Furthermore, studies with clinically relevant animal models have reached the same conclusion. Safi et alR3 showed that gene transfer of recombinant, secreted acidic fibroblast growth factor induces neovascularization in the normoperfused myocardium and subsequently reduces the risk region for myocardial infarction after coronary artery ligation. Our studyR4 showed that gene transfer of the 121-amino-acid form of vascular endothelial growth factor induces angiogenesis in nonischemic skeletal muscle, thus preserving tissue perfusion after the surgical induction of hindlimb ischemia. Similarly, Emanueli et alR5 showed that gene transfer of the human tissue kallikrein gene in normoperfused mouse hindlimb stimulates neovascularization in the transfected muscle.
Taken together, these results indicate that chronic ischemia is not a necessary precondition for new blood vessel development after administration of growth factors. This suggests that interventions aimed at inducing therapeutic angiogenesis need not be limited to patients with chronic myocardial ischemia or critical limb ischemia but may be extended to patients with stable exertional angina or intermittent claudication.
Simons M, Bonow RO, Chronos NA, et al. Clinical trials in coronary angiogenesis: issues, problems, consensus—an expert panel summary. Circulation. 2000;102:e73–e86.
Capogrossi MC, Passaniti A. An in vivo angiogenesis assay to study positive and negative regulators of neovascularization. In: AH Baker, ed. Vascular Disease: Molecular Biology and Gene Transfer Protocols. Totowa, NJ: Humana Press Inc; 1999:367–384.
Safi J Jr, DiPaula AF Jr, Riccioni T, et al. Adenovirus-mediated acidic fibroblast growth factor gene transfer induces angiogenesis in the nonischemic rabbit heart. Microvasc Res. 1999;58:238–249.
Gowdak LH, Poliakova L, Wang X, et al. Adenovirus-mediated VEGF121 gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia. Circulation.. 2000;102:565–571.
Emanueli C, Zacheo A, Minasi A, et al. Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscl Thromb Vasc Biol.. 2000;20:2379–2385.