Endothelial GATA-6 deficiency promotes pulmonary arterial hypertension

Am J Pathol. 2013 Jun;182(6):2391-406. doi: 10.1016/j.ajpath.2013.02.039. Epub 2013 Apr 11.


Pulmonary arterial hypertension (PAH) is a chronic and progressive disease characterized by pulmonary vasculopathy with elevation of pulmonary artery pressure, often culminating in right ventricular failure. GATA-6, a member of the GATA family of zinc-finger transcription factors, is highly expressed in quiescent vasculature and is frequently lost during vascular injury. We hypothesized that endothelial GATA-6 may play a critical role in the molecular mechanisms underlying endothelial cell (EC) dysfunction in PAH. Here we report that GATA-6 is markedly reduced in pulmonary ECs lining both occluded and nonoccluded vessels in patients with idiopathic and systemic sclerosis-associated PAH. GATA-6 transcripts are also rapidly decreased in rodent PAH models. Endothelial GATA-6 is a direct transcriptional regulator of genes controlling vascular tone [endothelin-1, endothelin-1 receptor type A, and endothelial nitric oxide synthase (eNOS)], pro-inflammatory genes, CX3CL1 (fractalkine), 5-lipoxygenease-activating protein, and markers of vascular remodeling, including PAI-1 and RhoB. Mice with the genetic deletion of GATA-6 in ECs (Gata6-KO) spontaneously develop elevated pulmonary artery pressure and increased vessel muscularization, and these features are further exacerbated in response to hypoxia. Furthermore, innate immune cells including macrophages (CD11b(+)/F4/80(+)), granulocytes (Ly6G(+)/CD45(+)), and dendritic cells (CD11b(+)/CD11c(+)) are significantly increased in normoxic Gata6-KO mice. Together, our findings suggest a critical role of endothelial GATA-6 deficiency in development and disease progression in PAH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / physiology
  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / biosynthesis
  • Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Case-Control Studies
  • Chronic Disease
  • Disease Progression
  • Down-Regulation / physiology
  • Endothelial Cells / physiology
  • Endothelium, Vascular / metabolism*
  • Familial Primary Pulmonary Hypertension
  • GATA6 Transcription Factor / deficiency*
  • GATA6 Transcription Factor / metabolism
  • GATA6 Transcription Factor / physiology
  • Gene Expression Regulation / physiology
  • Humans
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / metabolism*
  • Hypertrophy, Right Ventricular / metabolism
  • Hypertrophy, Right Ventricular / physiopathology
  • Hypoxia / complications
  • Lung / blood supply
  • Male
  • Mice
  • Mice, Knockout
  • Pneumonia / metabolism
  • RNA, Messenger / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Scleroderma, Systemic / complications


  • Arnt protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • GATA6 Transcription Factor
  • RNA, Messenger
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • endothelial PAS domain-containing protein 1