Fibroblast growth factor signals regulate a wave of hedgehog activation that is essential for coronary vascular development
Fibroblast growth factor signals regulate a wave of hedgehog activation that is essential for coronary vascular development
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DOI：
10.1101/gad.1411406
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发表时间：
2006-06-15
影响因子：
10.5
通讯作者：
Ornitz, David M.
中科院分区：
文献类型：
--
作者：
Lavine, Kory J.;White, Andrew C.;Ornitz, David M.
心肌梗塞和缺血性心脏病是工业世界的主要死亡原因。用于治疗这些疾病的疗法旨在促进增加流向心脏组织的血流。最近已经探索了新冠状动脉生长的药物诱导，然而，已知促血管生成因子的临床试验令人失望。为了确定新的治疗靶点，我们探索了控制胚胎冠状动脉发育的信号通路。使用基因工程小鼠和器官培养系统的组合，我们确定了成纤维细胞生长因子（FGF）和刺猬（HH）信号传导在冠状动脉血管发育中的新作用。我们发现，FGF信号通过Fgfr 1和Fgfr 2的冗余功能向成心肌细胞发出信号，间接促进冠状动脉生长。心肌FGF信号传导触发HH活化波，其对于血管内皮生长因子（Vegf）-A、Vegf-B、Vegf-C和血管生成素-2（Ang 2）表达是必需的。我们证明，HH是必要的冠状动脉血管的发展和激活HH信号足以促进冠状动脉生长和挽救冠状动脉缺损由于FGF信号的损失。这些研究表明HH信号传导是冠状动脉血管发育的重要调节因子，也是冠状动脉新生血管的潜在治疗靶点。与此一致，成人心脏中HH信号传导的激活导致冠状动脉血管密度增加。
Myocardial infarction and ischemic heart disease are the leading cause of death in the industrial world. Therapies employed for treating these diseases are aimed at promoting increased blood flow to cardiac tissue. Pharmacological induction of new coronary growth has recently been explored, however, clinical trials with known proangiogenic factors have been disappointing. To identify novel therapeutic targets, we have explored signaling pathways that govern embryonic coronary development. Using a combination of genetically engineered mice and an organ culture system, we identified novel roles for fibroblast growth factor (FGF) and Hedgehog (HH) signaling in coronary vascular development. We show that FGF signals promote coronary growth indirectly by signaling to the cardiomyoblast through redundant function of Fgfr1 and Fgfr2. Myocardial FGF signaling triggers a wave of HH activation that is essential for vascular endothelial growth factor (Vegf)-A, Vegf-B, Vegf-C, and angiopoietin-2 (Ang2) expression. We demonstrate that HH is necessary for coronary vascular development and activation of HH signaling is sufficient to promote coronary growth and to rescue coronary defects due to loss of FGF signaling. These studies implicate HH signaling as an essential regulator of coronary vascular development and as a potential therapeutic target for coronary neovascularization. Consistent with this, activation of HH signaling in the adult heart leads to an increase in coronary vessel density.