Phospholipid Growth Factors for Therapeutic Arteriogenesis and Tissue Engineering

本提案的重点是开发新的策略来促进成熟微血管的生长 通过治疗性诱导动脉生成形成的网络。动脉生成是指新的小动脉形成的过程 现有的小动脉在结构上扩大，有效地增加了阻力的数量和直径 微血管是外科移植或缺血性损伤后组织保存的关键。 初步研究表明，可生物降解的鞘氨醇-1-磷酸（S1 P） 聚合物在体内显著增强小动脉的管腔直径扩大;一个是微动脉的一个标志， 动脉生成S1 P是一种多效性自分泌和旁分泌信号小分子，其调节细胞的增殖和分化。 内皮细胞（EC）和平滑肌细胞（SMC）通过高亲和力G蛋白家族的行为- 偶联受体（S1 P1、S1 P2、S1 P3）。拟议活动的动机源于令人兴奋的新 S1 P受体的药理学激动剂和拮抗剂的合成进展。最近我们 证明了S1 P1的选择性药理学激动剂的体内递送显著增加 小动脉直径扩大和血管维持超过S1 P本身。S1 P1诱导 动脉生成表明，局部递送S1 P受体靶向药物以改善 组织工程和再生医学的治疗结果。为此，探索性实验现在 证明了植入可生物降解的三维（3D）支架选择性递送S1 P1， 化合物对临界大小的颅骨骨缺损显著增加骨组织向内生长， 骨修复组织中SMC投资微血管的比例。AIM 1将量化SMC的本地监管 增殖和管腔直径扩大的微血管网络在体内通过缓释 S1 P来自合成的可生物降解聚合物。目的2检验S1 P诱导的小动脉直径 增大需要SMC中S1 P1的激活。目的3测试假设，S1 P1诱导的调节， 微血管重塑将增强骨愈合结果。

The focus of this proposal is to develop new strategies to promote the growth of mature microvascular networks by therapeutic induction of arteriogenesis. Arteriogenesis is the process by which new arterioles form and existing arterioles structurally enlarge, effectively increasing the number and diameter of resistance microvessels that are critical to the preservation of tissues after surgical transplantation or ischemic injury. Preliminary studies show that sustained delivery of sphingosine-1-phosphate (S1P) from biodegradable polymers significantly enhances lumenal diameter enlargement of arterioles in vivo; one is one hallmark of arteriogenesis. S1P is a pleiotropic autocrine and paracrine signaling small molecule that regulates the behavior of endothelial cells (ECs) and smooth muscle cells (SMCs) through a family of high-affinity G protein- coupled receptors (S1P1, S1P2, S1P3). The motivation for the proposed activities stems from exciting new advances in the synthesis of pharmacological agonists and antagonists of S1P receptors. Recently, we demonstrated that in vivo delivery of selective pharmacological agonists of S1P1 significantly increases arteriolar diameter enlargement and vessel maintenance over S1P itself. The results of S1P1-induced arteriogenesis suggest exciting new possibilities for locally delivering S1P receptor targeted drugs to improve healing outcomes in tissue engineering and regenerative medicine. To this end, exploratory experiments now demonstrate that implantation of biodegradable three-dimensional (3D) scaffolds delivering S1P1 selective compounds to critical size calvarial bone defects significantly increases osseous tissue ingrowth and the proportion of SMC-invested microvessels in boney repair tissues. AIM 1 will quantify local regulation of SMC proliferation and lumenal diameter enlargement in microvascular networks in vivo via the sustained release of S1P from synthetic biodegradable polymers. AIM 2 tests the hypothesis that S1P-induced arteriolar diameter enlargement requires activation of S1P1 in SMCs. AIM 3 tests the hypothesis that S1P1-induced regulation of microvessel remodeling will enhance bone healing outcomes.