Related Experiment Video
Updated: Aug 9, 2026
11:38
Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay
Published on: September 14, 2021
Transforming growth factor-beta1-induced endothelial barrier dysfunction involves Smad2-dependent p38 activation and
Qing Lu1, Elizabeth O Harrington, Heather Jackson
1Vascular Research Laboratory, Providence VA Medical Center, Research Services, 151, 830 Chalkstone Ave., Providence, RI 02908, USA. Qing_Lu@brown.edu
Journal of Applied Physiology (Bethesda, Md. : 1985)
|April 29, 2006
Summary
Transforming growth factor-beta1 disrupts endothelial barrier function via Smad2-dependent p38 activation, leading to RhoA activation. This pathway contributes to acute lung injury and respiratory distress syndrome.
Area of Science:
- Cell biology
- Molecular biology
- Physiology
Background:
- Lung edema, characterized by increased vascular permeability, is a key feature of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).
- Both p38 and RhoA signaling pathways are implicated in transforming growth factor-beta1 (TGF-β1)-induced endothelial hyperpermeability, but their mechanistic interplay remains unclear.
Purpose of the Study:
- To investigate the role of Smad2 signaling in TGF-β1-induced endothelial permeability.
- To elucidate the sequential activation of p38 and RhoA signaling pathways by TGF-β1.
Main Methods:
- Endothelial cells were exposed to TGF-β1.
- Smad2 knockdown was performed using siRNA.
- Activation of p38 and RhoA signaling pathways was assessed.
- Inhibition of RhoA-Rho kinase and protein synthesis was utilized.
- Endothelial barrier integrity was evaluated by measuring monolayer permeability, adherens junction disruption, and focal adhesion complex formation.
Main Results:
- TGF-β1 induced Smad2 phosphorylation in endothelial cells.
- Smad2 knockdown abrogated TGF-β1-induced p38 activation and endothelial barrier dysfunction.
- TGF-β1-enhanced RhoA activation was dependent on p38 activation.
- Inhibition of RhoA-Rho kinase attenuated TGF-β1-induced adherens junction disruption and focal adhesion complex formation.
- Inhibition of de novo protein synthesis blocked TGF-β1-induced RhoA activation and barrier dysfunction.
Conclusions:
- TGF-β1 triggers endothelial barrier dysfunction through a Smad2-dependent activation of p38.
- Activated p38 subsequently leads to RhoA activation, potentially via transcriptional regulation.
- This signaling cascade contributes to the pathogenesis of lung edema in ALI and ARDS.
More Related Videos
Related Concept Videos
01:16TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
01:24Regulation of Angiogenesis and Blood Supply
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
01:24Small GTPases - Ras and Rho
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
01:07MAPK Signaling Cascades
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
01:19Interactions Between Signaling Pathways
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:22PI3K/mTOR/AKT Signaling Pathway
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a rapamycin-insensitive companion...