Role of mesenchymal-endothelial-transition in cardiac hypertrophy

描述（由申请人提供）：我们最近描述了一种新的生物学现象，我们称之为间充质-内皮细胞转化（MEndoT），即心脏损伤后瘢痕形成细胞表现出可塑性，并采用内皮细胞样的命运。成纤维细胞来源的内皮细胞有助于损伤后血管的形成，MEndoT的破坏加剧了损伤后血管的形成和修复。相比之下，MEndoT的增加减少了纤维化并增强了心脏修复，表明MEndoT作为急性心脏损伤的新治疗靶点的潜力。在更慢性的心脏损伤中，如心脏肥厚，新生血管的增加是心脏代偿反应的关键部分。新生血管增强见于初始代偿期，而血管退化和纤维化增加见于心力衰竭发展前的不适应期。新血管的破坏加速了心脏肥厚后心力衰竭的发展，而新血管的增强则延迟或延缓了心力衰竭的发展。然而，间充质-内皮转化是否发生在心脏肥厚中，是否可以作为延迟或延缓心力衰竭发展的治疗靶点尚不清楚。在本研究中，我们提供了心肌肥厚发生间质-内皮过渡的初步证据，并通过功能获得和功能丧失途径探讨MEndoT在心肌肥厚中的生理作用。我们的实验将为MEndoT在心脏肥厚中的生理作用提供新的见解，并可能确定MEndoT作为延缓心脏肥厚继发性心力衰竭的新靶点。

DESCRIPTION (provided by applicant): We have recently described a new biological phenomenon, we have termed mesenchymal-endothelial- transition (MEndoT), where scar forming cells in the heart, exhibit plasticity and adopt endothelial cell like fates after cardiac injury. Fibroblast derived endothelial cells contributed to post injury neovascularization and disruption of MEndoT worsened post injury neovascularization and repair. In contrast, augmentation of MEndoT decreased fibrosis and enhanced cardiac repair, demonstrating the potential of MEndoT as a novel therapeutic target in acute heart injury. In more chronic forms of cardiac injury such as cardiac hypertrophy, increased neovascularization is a critical part of the cardiac compensatory response. Enhanced neovascularization is seen in the initial compensatory phase while regression of vasculature and increased fibrosis are seen in the maladaptive phase prior to the development of heart failure. Disruption of neovascularization accelerates and enhanced neovascularization delays or retards the development of heart failure after cardiac hypertrophy. However whether mesenchymal-endothelial-transition occurs in cardiac hypertrophy and can serve as a therapeutic target for delaying or retarding the development of heart failure is not well understood. In this proposal we provide preliminary evidence that mesenchymal-endothelial transition occurs in cardiac hypertrophy and interrogate the physiological role of MEndoT in cardiac hypertrophy with gain and loss of function approaches. Our experiments will provide novel insight into the physiological role of MEndoT in cardiac hypertrophy and potentially identify MEndoT as a novel target for retarding heart failure secondary to cardiac hypertrophy.