Abstract 3602: Fibroblast Growth Factor-9 Stabilizes Angiogenesis and Generates Vasoresponsive Microvessels
Angiogenesis in adult, ischemic tissues can be of limited benefit because the endothelial-lined channels are neither durable nor capable of regulating blood flow. To stabilize newly formed vessels and impart vasoreactivity, mesenchymal cells must migrate to the microvessels and convert to contractile smooth muscle cells (SMCs). Using microarray analysis, we discovered that fibroblast growth factor 9 (FGF-9) was unique among all FGFs in that it was upregulated as immature SMCs migrated into chords and became contractile. To determine if FGF-9 impacted post-natal angiogenesis, growth factor-impregnated matrigel was injected subcutaneously in mice. Whereas FGF-2 stimulated robust angiogenesis, FGF-9 did not, as assessed by immunostaining for CD31. However, FGF-9 stimulated a pronounced recruitment of SM α-actin positive cells around endothelial tubes (83±8 vs 37±5% vessels wrapped, p<0.001). Reconstructed confocal images revealed a continuous layer of circumferentially wrapped SMCs. Three-dimensional CT microangiography revealed that perfusable microvessels extended deeper into matrigel constructs containing FGF-9 and FGF-2 than those with FGF-2 alone, suggesting a more cohesive microvascular network. Moreover, using a novel intravital microscopy technique, we found that FGF-9-modified microvessels contracted, reversibly, in response to phenylephrine, whereas FGF-2 alone-induced microvessels did not (52±9 vs. 4±3% diameter reduction). Organ culture of matrigel explants established that FGF-9 induced the differentiation of precursor cells recruited into the gel by FGF-2. FGF-9 also stimulated the expression of PGDFR-β in mesenchymal cells in vivo. Moreover, blockade of PDGFR-β in matrigel plugs with an inhibitory antibody attenuated FGF-9-induced investment of microves-sels with SM α-actin-expressing cells (87±4.3 vs 18±4.4%, p<0.05).
CONCLUSIONS: FGF-9 stimulates the formation of stable microvessels capable of responding to vasomotor control signals. Imparting new blood vessels with this degree of physiological responsiveness, which proceeds via a PDGFR-β-dependent mechanism, has not previously been identified in a tissue construct and has important implications for therapeutic angiogenesis.