Second Heart Field-Derived Cells Contribute to Angiotensin II-Mediated Ascending Aortopathies

Hisashi Sawada, Yuriko Katsumata, Hideyuki Higashi, Chen Zhang, Yanming Li, Stephanie Morgan, Lang H. Lee, Sasha A. Singh, Jeff Z. Chen, Michael K. Franklin, Jessica J. Moorleghen, Deborah A. Howatt, Debra L. Rateri, Ying H. Shen, Scott A. Lemaire, Masanori Aikawa, Mark W. Majesky, Hong S. Lu, Alan Daugherty

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background: The ascending aorta is a common location for aneurysm and dissection. This aortic region is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field SHF or the cardiac neural crest. SHF-derived cells populate areas that coincide with the spatial specificity of thoracic aortopathies. The purpose of this study was to determine whether and how SHF-derived cells contribute to ascending aortopathies. Methods: Ascending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin II AngII-infused mice. Ascending aortas without overt pathology from AngII-infused mice were subjected to mass spectrometry-assisted proteomics and molecular features of SHF-derived cells were determined by single-cell transcriptomic analyses. Genetic deletion of either Lrp1 low-density lipoprotein receptor-related protein 1 or Tgfbr2 transforming growth factor-β receptor type 2 in SHF-derived cells was conducted to examine the effect of SHF-derived cells on vascular integrity. Results: Pathologies in human ascending aortic aneurysmal tissues were predominant in outer medial layers and adventitia. This gradient was mimicked in mouse aortas after AngII infusion that was coincident with the distribution of SHF-derived cells. Proteomics indicated that brief AngII infusion before overt pathology occurred evoked downregulation of smooth muscle cell proteins and differential expression of extracellular matrix proteins, including several LRP1 ligands. LRP1 deletion in SHF-derived cells augmented AngII-induced ascending aortic aneurysm and rupture. Single-cell transcriptomic analysis revealed that brief AngII infusion decreased Lrp1 and Tgfbr2 mRNA abundance in SHF-derived cells and induced a unique fibroblast population with low abundance of Tgfbr2 mRNA. SHF-specific Tgfbr2 deletion led to embryonic lethality at E12.5 with dilatation of the outflow tract and retroperitoneal hemorrhage. Integration of proteomic and single-cell transcriptomics results identified PAI1 plasminogen activator inhibitor 1 as the most increased protein in SHF-derived smooth muscle cells and fibroblasts during AngII infusion. Immunostaining revealed a transmural gradient of PAI1 in both ascending aortas of AngII-infused mice and human ascending aneurysmal aortas that mimicked the gradient of medial and adventitial pathologies. Conclusions: SHF-derived cells exert a critical role in maintaining vascular integrity through LRP1 and transforming growth factor-β signaling associated with increases of aortic PAI1.

Original languageEnglish
Pages (from-to)987-1001
Number of pages15
JournalCirculation
Volume145
Issue number13
DOIs
StatePublished - Mar 29 2022

Bibliographical note

Funding Information:
The authors’ research work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL133723, R35HL15649 [Dr Daugherty], R01HL126901 [Dr Aikawa], R01HL149302 [Dr Aikawa], R01HL121877 [Dr Majesky]) and the American Heart Association Strategically Focused Research Network in Vascular Disease (18SFRN33960163 and 33960114). Dr Sawada was supported by an American Heart Association postdoctoral fellowship (18POST33990468). Dr Chen was supported by the National Center for Advancing Translational Sciences (UL1TR001998) and the National Heart, Lung, and Blood Institute (F30HL143943). Dr LeMaire is supported in part by the Jimmy and Roberta Howell Professorship in Cardiovascular Surgery at Baylor College of Medicine. The content in this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2022 American Heart Association, Inc.

Keywords

  • angiotensin
  • aortic aneurysm, thoracic
  • fibroblast
  • mice
  • smooth muscle

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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