Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis
Clare R. Ozawa, … , Donald M. McDonald, Helen M. Blau
Clare R. Ozawa, … , Donald M. McDonald, Helen M. Blau
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):516-527. https://doi.org/10.1172/JCI18420.
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Article Cardiology

Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis

Abstract

Use of long-term constitutive expression of VEGF for therapeutic angiogenesis may be limited by the growth of abnormal blood vessels and hemangiomas. We investigated the relationship between VEGF dosage and the morphology and function of newly formed blood vessels by implanting retrovirally transduced myoblasts that constitutively express VEGF164 into muscles of adult mice. Reducing VEGF dosage by decreasing the total number of VEGF myoblasts implanted did not prevent vascular abnormalities. However, when clonal populations of myoblasts homogeneously expressing different levels of VEGF were implanted, a threshold between normal and aberrant angiogenesis was found. Clonal myoblasts that expressed low to medium levels of VEGF induced growth of stable, pericyte-coated capillaries of uniform size that were not leaky and became VEGF independent, as shown by treatment with the potent VEGF blocker VEGF-TrapR1R2. In contrast, clones that expressed high levels of VEGF induced hemangiomas. Remarkably, when different clonal populations were mixed, even a small proportion of cells with high production of VEGF was sufficient to cause hemangioma growth. These results show for the first time to our knowledge that the key determinant of whether VEGF-induced angiogenesis is normal or aberrant is the microenvironmental amount of growth factor secreted, rather than the overall dose. Long-term continuous delivery of VEGF, when maintained below a threshold microenvironmental level, can lead to normal angiogenesis without other exogenous growth factors.

Authors

Clare R. Ozawa, Andrea Banfi, Nicole L. Glazer, Gavin Thurston, Matthew L. Springer, Peggy E. Kraft, Donald M. McDonald, Helen M. Blau

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The microenvironmental level of VEGF produced in muscle determines a thr...
The microenvironmental level of VEGF produced in muscle determines a threshold between the growth of normal capillaries and hemangiomas. (a) Morphology of vessels at sites of implanted LacZ control cells (Control) and of different VEGF clones at 4 weeks (n = 3–7 per group). Clones 10%, 50%, and 100% produced small-caliber vessels resembling capillaries. Although vessels at sites implanted with 100% clones were uneven in diameter in some regions (arrows), no abnormal bulbous structures were observed in these ears. Aberrant bulbous vascular structures were present in ears implanted with the 180% clone (arrowheads). Large hemangiomas developed in ears implanted with the 325% clone by 4 weeks (H&E stain). (b) The corresponding distributions of vessel diameters at implantation sites are shown below each panel. (c) Morphologies of vessels at sites implanted with the same clones at 2.5–3.5 months after implantation. The capillaries induced by the 10%, 50%, and 100% clones persisted and did not develop any abnormalities, whereas hemangiomas grew in ears implanted with the 180% clone after 2.5 months (H&E stain). The vertical red line and the arrow at the bottom indicate the threshold between the induction of normal capillaries and hemangiomas at a VEGF level between that produced by the 100% and 180% clones. Scale bars: 50 μm (lectin panels, far right in a and c), 1 mm (H&E panel in a), and 0.5 mm (H&E panel in c).