Microenvironmental VEGF distribution is critical for stable and functional vessel growth in ischemia

Abstract

The critical role of vascular endothelial growth factor (VEGF) expression levels in developmental angiogenesis is well established. Nonetheless, the effects of different local (microenvironmental) VEGF concentrations in ischemia have not been studied in the adult organism, and VEGF delivery to patients has been disappointing. Here, we demonstrate the existence of both lower and upper threshold levels of microenvironmental VEGF concentrations for the induction of therapeutic vessel growth in ischemia. In the ischemic hind limb, implantation of myoblasts transduced to express VEGF164 at different levels per cell increased blood flow only moderately, and vascular leakage and aberrant preangiomatous vessels were always induced. When the same total dose was uniformly distributed by implanting a monoclonal population derived from a single VEGF-expressing myoblast, blood flow was fully restored to nonischemic levels, collateral growth was induced, and ischemic damage was prevented. Hemangiomas were avoided and only normal, pericyte-covered vessels were induced persisting over 15 mo. Surprisingly, clones uniformly expressing either lower or higher VEGF levels failed to provide any functional benefit. A biphasic effect of VEGF dose on vessel number and diameter was found. Blood flow was only improved if vessels were increased both in size and in number. Microenvironmental VEGF concentrations determine efficacy and safety in a therapeutic setting.

Active Rac1 improves pathologic VEGF neovessel architecture and reduces vascular leak: mechanistic similarities with angiopoietin-1

“…Moreover, these vascular defects seriously limit the use of VEGF as therapeutic agent for tissue revascularization. [15][16][17][18] Although proangiogenic therapy with VEGF can increase blood flow in experimental models, the positive effects of VEGF are compromised by vascular malformations and vascular leak. 17,18 Accordingly, our studies with SEW2871, an S1P 1 agonist, Rac1 activator, 33 and persistent inducer of cortical actin and enhanced EC-EC junction integrity, identify a rational drug-based strategy for correcting these neovascular defects.…”

“…[15][16][17][18] Although proangiogenic therapy with VEGF can increase blood flow in experimental models, the positive effects of VEGF are compromised by vascular malformations and vascular leak. 17,18 Accordingly, our studies with SEW2871, an S1P 1 agonist, Rac1 activator, 33 and persistent inducer of cortical actin and enhanced EC-EC junction integrity, identify a rational drug-based strategy for correcting these neovascular defects. Furthermore, findings with SEW2871 suggest more generally that pharmacologic strategies involving other S1P 1 agonists or other Rac1 activators that organize cortical actin and improve EC-EC junction integrity persistently could be used effectively to improve pathologic angiogenesis and promote therapeutic angiogenesis with VEGF.…”

“…12 Serious neovascular malformations and vascular leak also have been observed in various animal models designed to test proangiogenic therapy with VEGF. [15][16][17][18] Nonetheless, the underlying fundamentals responsible for abnormal VEGF neovascularization have been largely unexplored. Experiments described here illustrate that active Rac1 markedly improves the angioarchitecture and reduces leakiness of pathologic neovessels induced by VEGF.…”

Myoblast-Mediated Gene Therapy Improves Functional Collateralization in Chronic Cerebral Hypoperfusion

“…[14][15][16][17] In this regard, experimental studies in nonischemic and ischemic tissue have evidenced that an appropriate microenvironmental VEGF concentration is paramount for induction and maintenance of functional neovascularization at a desired target site. 18,19 Hence, the DNA transfer to myogenic precursor cells seems to be an ideal drug delivery strategy to ensure a consistent, long-term and regionally circumscribed overexpression of VEGF for effective induction of neovascularization at the muscle/brain interface of an EMS. Recently, we demonstrated the general feasibility of this approach by successful implantation and fusion of primary monoclonal mouse myoblasts in the nonischemic temporal muscle of an experimental EMS.…”

Gene Therapy and Stem Cell Therapy to Improve the Outcome of Human Islet Transplantation

“…Therefore, in Adv-transduced human islet clusters, growth factor concentration in extracellular microenvironment could not be uniformly distributed and finely regulated. Accumulation of microenvironmental VEGF in the outer layer of human islets may finally lead to aberrant angiogenesis and islet loss [10,104].…”