Upregulation Of Transforming Growth Factor Research Articles

Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction.

Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown. To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction. ETS1 global and endothelial-specific knockout mice were used. Phenotypic assessments, RNA sequencing, and chromatin immunoprecipitation analysis were performed together with expression analysis, immunofluorescence and RNAscope in situ hybridization to uncover phenotypic and transcriptomic changes in response to loss of ETS1. Loss of ETS1 in endothelial cells causes ventricular noncompaction, reproducing the phenotype arising from global deletion of ETS1. Endothelial-specific deletion of ETS1 decreased the levels of Alk1 (activin receptor-like kinase 1), Cldn5 (claudin 5), Sox18 (SRY-box transcription factor 18), Robo4 (roundabout guidance receptor 4), Esm1 (endothelial cell specific molecule 1) and Kdr (kinase insert domain receptor), 6 important angiogenesis-relevant genes in endothelial cells, causing a coronary vasculature developmental defect in association with decreased compact zone cardiomyocyte proliferation. Downregulation of ALK1 expression in endocardium due to the loss of ETS1, along with the upregulation of TGF (transforming growth factor)-β1 and TGF-β3, occurred with increased TGFBR2/TGFBR1/SMAD2 signaling and increased extracellular matrix expression in the trabecular layer, in association with increased trabecular cardiomyocyte proliferation. These results demonstrate the importance of endothelial and endocardial ETS1 in cardiac development. Delineation of the gene regulatory network involving ETS1 in heart development will enhance our understanding of the molecular mechanisms underlying ventricular and coronary vascular developmental defects and will lead to improved approaches for the treatment of patients with congenital heart disease.

A matrix for new ideas in pulmonary fibrosis.

Pulmonary fibrosis is a progressive and ultimately fatal condition, characterized pathologically by mesenchymal cell proliferation in the lung, expansion of the extracellular matrix (ECM), and extensive remodeling of the lung parenchyma. Although the pathogenesis of this disease is complex and poorly understood, growth factors, cytokines, chemokines, and regulators of apoptosis have all been implicated in its progression. Pulmonary fibrosis has been traditionally viewed as a consequence of inflammation, but this interpretation has been questioned in recent years because clinical measures of inflammation do not correlate well with disease progression and because anti-inflammatory drugs do not significantly affect clinical outcome. For these reasons, recent attention has focused on the ECM and molecules that normally regulate its homeostasis. Among the molecules thought to regulate matrix deposition, transforming growth factor (TGF)- � 1 is probably the best-studied. This fibrogenic growth factor is upregulated in lung parenchyma from patients with idiopathic pulmonary fibrosis (1), it increases the production of collagen and other extracellular matrix components (2‐4), and it regulates the expression of other genes associated with ECM degradation and proteolysis. Moreover, adenoviral delivery of active TGF- � 1 to rat lung results in architectural changes similar to those seen in pulmonary fibrosis (5). Other studies have revealed that overexpression of granulocyte macrophage‐colony stimulating factor (2), tumor necrosis factor- � (3), and interleukin-13 (4) also result in myofibroblast proliferation and ECM deposition. Interestingly, a common feature among these latter studies is the upregulation of TGF- � 1 expression in the lung, further supporting the hypothesis that this cytokine plays an important role in pulmonary fibrosis. Additional evidence for the importance of TGF- � 1 in pulmonary fibrosis is provided by the observation that TGF- � 1 may play a role in susceptibility to fibrogenic agents in mice. For example, expression of TGF- � 1 in the