Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis
J. Clin. Invest. Clare R. Ozawa, et al. 113:516 doi:10.1172/JCI18420 [Go to this article.]

Figure 1
Uncontrolled VEGF production promotes abnormal vascular growth in muscle. (a) Myoblasts expressing both VEGF₁₆₄ and LacZ or control LacZ myoblasts were implanted into the posterior auricular muscles of mice (crossmarks). (b) X-gal staining of a control ear sectioned along the dashed line in a at 14 days after implantation, showing LacZ myoblasts fused into endogenous myofibers (arrowheads) and clusters of unfused myoblasts or myoblasts fused with each other (arrows; n = 7). (c) Lectin and X-gal staining of control ear bisected in the plane of the cartilage, showing LacZ-positive myofibers at the site of injection at 28 days (arrow; n = 10). (d) Vessels at sites of implanted control myoblasts were normal at all time points (18 hours and 4, 7, 14, 28, and 64 days; n = 10 for each time point). (e) At 7 days after implantation of VEGF myoblasts, vessels leading into the injection site (arrows) became enlarged (n = 9). (f) At 28 days after implantation, aberrant bulbous structures (left arrow) and bundles of capillary-like vessels (right arrow) were present at sites of implanted VEGF myoblasts (n = 10). (g) At day 64, typical large blood-filled growths (hemangiomas) developed in ears implanted with VEGF myoblasts (left). The contralateral control ear was normal (n = 10). (h) H&E staining of an ear containing a hemangioma (top) and of a control ear (bottom). (i) A vessel leading into the injection site (arrow) became abnormal in the immediate vicinity of implanted VEGF myoblasts (from a second VEGF myoblast population, VEGF*; 7 days after implantation). Scale bars: 100 μm (b), 1 mm (c and h), and 50 μm (d–f and i).