Pulmonary Vascular Tree Development, Growth & Remodling

描述（由申请人提供）：肺血管树具有独特的设计，可优化气体交换的血流分布。在正常情况下，它的几何形状是胎儿发育和出生后生长的最终产物。在疾病中，通过血管重塑发生进一步的重组。分子和细胞生物学的最新进展为这三个决定因素如何在细胞水平上影响血管结构提供了见解。这项工作将生理学研究与原位细胞和分子技术相结合，以确定这些因子在整个活体动物中的功能意义。 具体目标1：确定胎儿发育过程中肺血管树生长的遗传控制程度及其几何形状如何随出生后生长而变化。我们将使用犰狳，一种独特的动物，产生相同的后代。通过比较窝内和窝间血流的空间分布，我们可以量化遗传对血管树发育和区域灌注的影响。我们还将测量生长猪的局部血流，以确定血流再分布的模式。空间聚集的模式将提供证据表明，出生后的肺血管树的生长可能是局部调节。 具体目标2：确定慢性缺氧期间肺血管重塑的触发因素。我们将重点研究机械应力在促进大鼠肺动脉细胞增殖和凋亡中的作用。 具体目标3：在血管内皮生长因子受体-1抑制诱导的肺动脉高压中确定肺血管重构的触发因素。我们将重点讨论机械性室壁应力在促进丛状病变中的作用，丛状病变是原发性肺动脉高压的特征。 拟议的工作旨在确定器官水平肺循环中功能，结构和遗传控制之间的关系。最新的和 这项工作的重要方面是将在完整的动物中探索细胞和分子机制。这些发现将填补我们对肺血管发育和重塑触发因素的认识的重要空白。

DESCRIPTION (provided by applicant): The pulmonary vascular tree has a unique design that optimizes the distribution of blood flow for gas exchange. Under normal conditions, its geometry is an end product of fetal development and postnatal growth. In disease, further restructuring occurs through vascular remodeling. Recent advances in molecular and cellular biology provide insights into how these three determinants influence vascular structure at the cellular level. The proposed work integrates physiologic studies with in situ cellular and molecular techniques to determine the functional significance of these factors in the whole living animal. Specific aim 1: Determine the degree of genetic control on pulmonary vascular tree growth during fetal development and how its geometry changes with postnatal growth. We will use armadillos, a unique animal that produces litters of identical offspring. By comparing the spatial distribution of blood flow within and across litters, we can quantify the genetic influence on vascular tree development and regional perfusion. We will also measure regional blood flow in growing pigs to identify patterns of blood flow redistribution. Patterns that are spatially clustered will provide evidence that postnatal growth of the pulmonary vascular tree may be locally regulated. Specific aim 2: Identify triggers of pulmonary vascular remodeling during chronic hypoxia. We will focus on the roles of mechanical wall stresses in promoting cellular proliferation and apoptosis in rat pulmonary arteries. Specific aim 3: Identify triggers of pulmonary vascular remodeling in pulmonary hypertension induced by vascular endothelial growth factor receptor-1 inhibition. We will focus on the roles of mechanical wall stresses in promoting plexiform lesions that are characteristic of primary pulmonary hypertension. The proposed work is designed to determine relationships between function, structure and genetic controls in the pulmonary circulation at the organ level. The most novel and significant aspect of the work is that cellular and molecular mechanisms will be explored in the intact animal. The findings will fill important gaps in our knowledge of pulmonary vascular development and triggers of remodeling.