Ischemia of the myocardium and lower limbs is a common consequence of arterial disease and a major source of morbidity and mortality in modernized countries. Inducing neovascularization for the treatment of
ischemia is an appealing therapeutic strategy for patients for whom traditional treatment modalities cannot be performed or are ineffective. In the past, the stimulation of blood vessel growth was pursued using direct delivery of
growth factors, angiogenic gene therapy, or cellular
therapy. Although therapeutic angiogenesis holds great promise for treating patients with
ischemia, current methods have not found success in clinical trials.
Fibroblast growth factor-2 (FGF-2) was one of the first
growth factors to be tested for use in therapeutic angiogenesis. Here, we present a method for improving the
biological activity of
FGF-2 by codelivering the
growth factor with a liposomally embedded coreceptor,
syndecan-4. This technique was shown to increase
FGF-2 cellular signaling, uptake, and nuclear localization in comparison with
FGF-2 alone. Delivery of
syndecan-4 proteoliposomes also increased endothelial proliferation, migration, and angiogenic tube formation in response to
FGF-2. Using an animal model of limb
ischemia,
syndecan-4 proteoliposomes markedly improved the neovascularization following femoral artery
ligation and recovery of perfusion of the ischemic limb. Taken together, these results support liposomal delivery of
syndecan-4 as an effective means to improving the potential of using
growth factors to achieve therapeutic neovascularization of ischemic tissue.