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Functional Role of Second Heart Field-derived Cells in Aortic Integrity in Mice

The ascending aorta is a common location for thoracic aortopathies. Pathology predominates in the aortic media with disease severity being most apparent in outer laminar layers of the ascending aorta. Smooth muscle cells (SMCs) and selected fibroblasts in these regions are derived from second heart field (SHF). SHF-derived cells have a distinct distribution, and the localization of SHF coincides with the regional specificity in some forms of thoracic aortopathies. However, the role of SHF-derived cells in maintaining the structural and functional integrity of the ascending aorta remains unclear.Mass spectrometry assisted proteomic and single cell transcriptomic analyses were performed in angiotensin (AngII)-infused mouse aortas to investigate the molecular mechanism of the regional specificity of thoracic aortopathies and discriminate molecular features of SHF-derived cells in maintaining the aortic homeostasis. Genetic deletion of either transforming growth factor-β receptor 2 (Tgfbr2) or low-density lipoprotein receptor-related protein 1 (Lrp1) in SHF-derived cells was conducted to examine the impact of SHF-derived cells on the integrity of aortic wall.Proteomic analysis identified the alteration of protein profiles by AngII infusion in a region-specific manner. AngII evoked differential expression of multiple proteins related to extracellular matrix organization. Histological analysis demonstrated that AngII-induced medial disruptions were predominantly in the outer laminar layers derived from the SHF. Single cell transcriptomic analysis revealed that elastin, a major component of extracellular matrix, was less abundant in SHF-derived SMCs and fibroblasts compared to those from other origins. In addition, mRNA of Tgfbr2 and Lrp1, key molecules for extracellular maturation, were abundant in SHF-derived SMCs of control aortas. AngII infusion decreased Lrp1 mRNA abundance. To examine biological effects of SHF-derived cells, either TGFBR2 or LRP1 were deleted in SHF-derived cells in mice. SHF-specific TGFBR2 deletion led to embryonic lethality at E12.5 with dilatation of the outflow tract and retroperitoneal hemorrhage in mice. LRP1 deletion in SHF-derived cells augmented AngII-induced aortic aneurysm and rupture in the ascending region.These results demonstrate that SHF-derived cells exert a critical role in maintaining the integrity of the ascending aorta in mice.