Small molecule inducers of angiogenesis for tissue engineering.
ABSTRACT Engineering of implantable tissues requires rapid induction of angiogenesis to meet the significant oxygen and nutrient demands of cells during tissue repair. To this end, our laboratories have utilized medicinal chemistry to synthesize non-peptide-based inducers of angiogenesis to aid tissue engineering. In this study, we describe the evaluation of SC-3-149, a small molecule compound with proliferative effects on vascular endothelial cells. Specifically, exogenous exposure of SC-3-149 induced an 18-fold increase in proliferation of human microvascular endothelial cells in vitro at low micromolar potency by day 14 in culture. Moreover, SC-3-149 significantly increased the formation of endothelial cord and tubelike structures in vitro, and improved endothelial scratch wound healing within 24 h. SC-3-149 also significantly inhibited vascular endothelial cell death owing to serum deprivation and high acidity (pH 6). Concurrent incubation of SC-3-149 with vascular endothelial growth factor increased cell survivability under serum-deprived conditions by an additional 7%. In addition, in vivo injection of SC-3-149 into the rat mesentery produced qualitative increases in microvessel length density. Taken together, our studies suggest that SC-3-149 and its analogs may serve as promising new angiogenic agents for targeted drug delivery and therapeutic angiogenesis in tissue engineering.
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ABSTRACT: Promoting the formation of new collateral vessels in ischemic tissues using angiogenic growth factors (therapeutic angiogenesis) is a an exciting frontier of cardiovascular medicine. Conversely, inhibition of the action of key regulators of angiogenesis, such as VEGF, constitutes a promising approach for the treatment of solid tumors and intraocular neovascular syndromes. These concepts are being tested now in clinical trials.Nature Medicine 01/2000; 5(12):1359-64. · 22.86 Impact Factor
- Science 09/1998; 281(5380):1161-2. · 31.03 Impact Factor
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ABSTRACT: To gain insight into how a naturally occurring scaffold composed of extracellular matrix (ECM) proteins provides directional guidance for capillary sprouting, we examined angiogenesis in whole-mount specimens of rat mesentery. Angiogenesis was studied in response to normal maturation, the injection of a mast cell degranulating substance (compound 48/80), and mild wounding. Confocal microscopy of specimens immunolabeled for elastin revealed a network of crosslinked elastic fibers with a density of 140.8 +/- 37 mm of fiber/mm(2) tissue. Fiber diameters ranged from 180 to 1400 nm, with a mean value of 710 +/- 330 nm. Capillary sprouts contained CD31- and OX-43-positive endothelial cells as well as desmin-positive pericytes. During normal maturation, leading endothelial cells and pericytes were in contact and aligned with an elastic fiber in approximately 80-90% of all sprouts. In wounding and compound 48/80-treated specimens, in which angiogenesis was markedly increased, leading endothelial cells remained in contact and aligned with elastic fibers in approximately 60-80% of all sprouts. These observations indicate that elastic fibers are used for endothelial and pericyte migration during capillary sprouting in rat mesentery. The composition of this elastic fiber matrix may provide important clues for the development of tissue-engineered scaffolds that support and directionally guide angiogenesis.Journal of Histochemistry and Cytochemistry 09/2004; 52(8):1063-72. · 2.26 Impact Factor