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Lineage interactions during heart development.

机译：心脏发育过程中的血统相互作用。

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摘要

Variations in coronary artery anatomy are associated with a number of congenital heart diseases. Knowledge of how the coronary circulation is established is essential for understanding how these congenital defects occur. The coronary ostium are the origins of the two primary coronary arteries and their abnormal development leads to vascular defects yet little is known how they form in mammals. We examined how ostia form in mice and found that a small population of endothelial cells migrate to the aorta where they penetrate to first form the left ostia followed by the right ostia. The ostia increase their diameter by recruiting endothelial cells and extramural cells. After remodeling, the coronary ostia allows blood to flow through the coronary arteries and the accompanying shear stress of the circulation promotes growth and bifurcation of the arteries.;During our investigation of the developmental roles of the bHLH transcription factor Hand1, we found that the loss of Hand1 in neural crest resulted in mis-patterning of the coronary arteries. Loss of Hand1 does not affect cardiac neural crest's ability to populate the heart nor cause significant defects in the outflow tract. We show that Hand1 loss does not affect vasculogenesis but causes defects during angiogenesis in the heart that can be attributed to defective coronary ostia development. Comparing embryos with a deletion of Hand1 in neural crest to normal development, we show that loss of Hand1 leads to ectopic endothelial cells around the ostia and formation of accessory ostia. Mutant hearts display either complete disorganization of the coronary arteries or arteries with an increased luminal diameter. Mutant embryonic hearts also show a decrease in density of vascular network branching. Similarly, latex and corrosion cast injections in adult hearts show a decrease in microvasculature in mutant hearts. To begin addressing the molecular basis of the ostia defects in the Hand1 mutant embryos, we examined the expression of genes known to cause ostia defects. We examined the expression levels of Vegf-A, Vegf-B, Pdgf-BB, and Fgf-2 transcript and found that Vegf-A is up-regulated in the mutant hearts. Our analysis shows for the first time that in addition to the previously known functions of neural crest in heart development, they also play a role in coronary vascular development by regulating ostia formation.;Coordinated contraction of the ventricular myocardium is essential for heart function. The cardiac conduction system (CCS) is responsible for coordinating contraction with developmental defects resulting in embryonic lethality or a predisposition to arrhythmias post-natally. The CCS is derived from working cardiomyocytes that reside adjacent to the endocardium suggesting that the endocardium promotes the trans-differentiation of myocardial cells into Purkinje fiber cells of the CCS. A possible mechanism by which the endocardium signals to the myocardium is by endothelin (ET) signaling.;ET peptide binds to one of the two G-protein coupled receptors (GPCRs) known as endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB). An examination of receptor distribution showed they are expressed in different cell compartments. We simultaneously inactivated the genes encoding the endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) in mice to determine if their loss resulted in novel cardiovascular defects. We found that double knockout (DKOs) embryos die at birth from mechanical asphyxia due to severe malformation of neural crest-derived facial and throat structures. Comparing hearts with deletions of both endothelin receptors to single Ednra and Ednrb nulls showed the DKO and single Ednrb null hearts have more severe thinning of their myocardial walls as compared to single Ednra nulls. The hearts have a thin myocardial wall but no obvious morphological CCS defects. Examining genes known to cause myocardial and conduction system defects we found an up-regulation of Irx3, Irx5, and Bmp10. Our analysis shows for the first time that endothelin receptors are not required for proper cardiac conduction system formation and are expressed in different cell compartments in the heart.
机译：冠状动脉解剖结构的变化与许多先天性心脏病有关。要了解这些先天性缺陷是如何发生的，必须了解如何建立冠状动脉循环。冠状动脉口是两条主要冠状动脉的起源，它们的异常发育会导致血管缺陷，但在哺乳动物中如何形成它们却鲜为人知。我们检查了小鼠中眼口的形成方式，发现一小部分内皮细胞迁移到主动脉，然后在它们穿透后首先形成左眼口，然后形成右眼口。孔口通过募集内皮细胞和壁外细胞来增加直径。重塑后，冠状动脉口使血液流过冠状动脉，伴随的循环剪切应力促进了动脉的生长和分支。在我们研究bHLH转录因子Hand1的发育作用时，我们发现Hand1在神经c中的形成导致冠状动脉的图案错误。 Hand1的丢失不会影响心脏神经c充盈心脏的能力，也不会引起流出道的重大缺陷。我们显示Hand1损失不会影响血管生成，但会导致心脏血管生成过程中的缺陷，这可归因于冠状动脉口发育不良。比较在神经rest中Hand1缺失的胚胎与正常发育的情况，我们发现Hand1的缺失导致异位口周围的异位内皮细胞形成。变异的心脏显示出冠状动脉完全紊乱或管腔直径增加的动脉。突变的胚胎心脏也显示出血管网络分支密度的降低。同样，成年心脏中的乳胶和腐蚀铸模注射显示突变心脏中微血管的减少。为了解决Hand1突变体胚胎中口孔缺损的分子基础，我们检查了已知引起口孔缺损的基因的表达。我们检查了Vegf-A，Vegf-B，Pdgf-BB和Fgf-2转录本的表达水平，发现Vegf-A在突变体心脏中上调。我们的分析首次表明，除了神经known在心脏发育中的先前已知功能外，它们还通过调节孔口形成在冠状血管发育中发挥作用。；心室心肌的协调收缩对于心脏功能至关重要。心脏传导系统（CCS）负责协调收缩与发育缺陷，导致胚胎致死或产后心律失常的易感性。 CCS源自驻留在心内膜附近的正常心肌细胞，这表明心内膜可促进心肌细胞向CCS的Purkinje纤维细胞的反分化。心内膜向心肌发出信号的可能机制是通过内皮素（ET）信号传导。ET肽与称为内皮素受体A（EDNRA）和内皮素受体B（EDNRB）的两个G蛋白偶联受体（GPCR）之一结合）。检查受体分布表明它们在不同的细胞区室中表达。我们同时灭活了小鼠中编码内皮素受体A（EDNRA）和内皮素受体B（EDNRB）的基因，以确定它们的丢失是否导致新的心血管缺陷。我们发现双敲除（DKO）胚胎在出生时因机械性窒息死亡，原因是神经rest衍生的面部和喉咙结构严重畸形。将具有两种内皮素受体缺失的心脏与单一的Ednra和Ednrb缺失进行比较，发现与单一的Ednra缺失相比，DKO和单一的Ednrb缺失心脏的心肌壁更薄。心脏的心肌壁薄，但没有明显的CCS形态学缺陷。检查已知会引起心肌和传导系统缺陷的基因，我们发现Irx3，Irx5和Bmp10上调。我们的分析首次表明，内皮素受体不是正确的心脏传导系统形成所必需的，它们在心脏的不同细胞区室中表达。

著录项

  • 作者

    Hua, Lisa.;

  • 作者单位

    Tulane University School of Science and Engineering.;

  • 授予单位 Tulane University School of Science and Engineering.;
  • 学科 Biology Cell.;Biology Physiology.;Health Sciences Human Development.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 99 p.
  • 总页数 99
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 物理化学（理论化学）、化学物理学;
  • 关键词

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