Published Online
on December 12, 2005

A more recent version of this article appeared on December 20, 2005

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Submitted on February 15, 2005
Revised on October 4, 2005
Accepted on October 11, 2005

Blood Flow Remodels Growing Vasculature During Vascular Endothelial Growth Factor Gene Therapy and Determines Between Capillary Arterialization and Sprouting Angiogenesis

Tuomas T. Rissanen MD, PhD, Petra Korpisalo MD, Johanna E. Markkanen MD, Timo Liimatainen MSc, Maija-Riitta Ordén MD, PhD, Ivana Kholová MD, PhD, Anna de Goede MSc, Tommi Heikura MSc, Olli H. Gröhn PhD, and Seppo Ylä-Herttuala MD, PhD, FESC^*

From the Departments of Biotechnology and Molecular Medicine (T.T.R., P.K., J.E.M., I.K., A.d.G., T.H., S.Y.-H.) and Biomedical NMR and National Bio NMR Facility (T.L., O.H.G.), A.I. Virtanen Institute, Kuopio University; Department of Gynecology and Obstetrics, Kuopio University Hospital (M.O.); Department of Medicine, Kuopio University (S.Y.-H.); and Gene Therapy Unit, Kuopio University Hospital (S.Y.-H.), Kuopio, Finland.

^* To whom correspondence should be addressed. E-mail: Seppo.Ylaherttuala{at}uku.fi.

Background--For clinically relevant proangiogenic therapy, it would be essential that the growth of the whole vascular tree is promoted. Vascular endothelial growth factor (VEGF) is well known to induce angiogenesis, but its capability to promote growth of larger vessels is controversial. We hypothesized that blood flow remodels vascular growth during VEGF gene therapy and may contribute to the growth of large vessels.

Methods and Results--Adenoviral (Ad) VEGF or LacZ control gene transfer was performed in rabbit hindlimb semimembranous muscles with or without ligation of the profound femoral artery (PFA). Contrast-enhanced ultrasound and dynamic susceptibility contrast MRI demonstrated dramatic 23- to 27-fold increases in perfusion index and a strong decrease in peripheral resistance 6 days after AdVEGF gene transfer in normal muscles. Enlargement by 20-fold, increased pericyte coverage, and decreased alkaline phosphatase and dipeptidyl peptidase IV activities suggested the transformation of capillaries toward an arterial phenotype. Increase in muscle perfusion was attenuated, and blood vessel growth was more variable, showing more sprouting angiogenesis and formation of blood lacunae after AdVEGF gene transfer in muscles with ligated PFA than in normal muscles. Three-dimensional ultrasound reconstructions and histology showed that the whole vascular tree, including large arteries and veins, was enlarged manifold by AdVEGF. Blood flow was normalized and enlarged collaterals persisted in operated limbs 14 days after AdVEGF treatment.

Conclusions--This study shows that (1) blood flow modulates vessel growth during VEGF gene therapy and (2) VEGF overexpression promotes growth of arteries and veins and induces capillary arterialization leading to supraphysiological blood flow in target muscles.

Key words: angiogenesis • gene therapy • ischemia • perfusion • peripheral vascular disease

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