Figure - PMC

Skip to main content

An official website of the United States government

Here's how you know

Here's how you know

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

View full-text article in PMC

. 2020 May 13;217(7):e20192205. doi: 10.1084/jem.20192205

Search in PMC
Search in PubMed
View in NLM Catalog
Add to search

© 2020 Janardhan et al.

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

PMC Copyright notice

Figure 4. — Pharmacologic inhibition of Braf^V600E-Map2k or genetic ablation of Mapk1 rescue hepatic vascular cavernomas in Braf^{V600E F/+}; Lyve1^Cre and Kras^{G12D F/+}; Lyve1^Cre mice. (A and B) Dissected Braf^{V600E F/+}; Lyve1^Cre littermate embryos treated with dabrafenib and trametinib (A) or lacking Mapk1 (B) show rescued liver size (green arrows) compared with Braf^{V600E F/+}; Lyve1^Cre embryos (yellow arrow; n = 3). H&E-stained or Lyve1 (green), Pecam1 (red), and Hoechst (blue) coimmunofluorescent–stained liver sections of Braf^{V600E F/+}; Lyve1^Cre littermate embryos treated with dabrafenib and trametinib (A) or lacking Mapk1 (B) show normal sinusoidal capillaries (green arrows) compared with cavernous sinusoids in Braf^{V600E F/+}; Lyve1^Cre embryos (yellow arrows; n = 3). Immunofluorescent staining on liver sections of Braf^{V600E F/+}; Lyve1^Cre embryos treated with dabrafenib and trametinib (A) or lacking Mapk1 (B) show normal button-like discontiguous expression of Cdh5 (brown arrows) compared with abnormal zipper-like contiguous expression of Cdh5 in Braf^{V600E F/+}; Lyve1^Cre embryos (red arrows; n = 3). White arrows show normal button-like discontiguous expression of Cdh5 in control livers. Scale bars: 500 µm (top row), 1,000 µm (second row from top), 100 µm (third, fourth, and sixth rows from top), and 10 µm (fifth and seventh rows from top). Two independent experiments. (C) Dissected Kras^{G12D F/+}; Lyve1^Cre littermate embryos lacking Mapk1 show rescued liver size (green arrow), normal sinusoidal capillaries (green arrows) stained with H&E or Lyve1 (green) and Pecam1 (red), and normal button-like discontiguous expression of Cdh5 (brown arrows) compared with Kras^{G12D F/+}; Lyve1^Cre (yellow and red arrows). n = 3. Scale bars: 500 µm (first column from left), 1,000 µm (second column from left), 100 µm (third, fourth, and sixth columns from left), and 10 µm (fifth and seventh columns from left). Two independent experiments. (D) Endothelial activating KRAS or BRAF mutations drive hepatic vascular cavernomas via MAP2K–MAPK1 signaling pathway. Proposed model suggesting that constitutive activation of KRAS–BRAF–MAP2K–MAPK1 signaling pathway in sinusoidal endothelial cells promotes aberrant zipper-like contiguous expression of adherens junctional proteins, such as Cdh5, switching hepatic sinusoidal capillaries from branching to cavernous expansion. All experimental data verified in at least two independent experiments. CdRL, caudal right lobe; CL, caudate lobe; CrRL, cranial right lobe; LK, left kidney; LL, left lobe; LML, left medial lobe; LV, left ventricle; RK, right kidney; RML, right medial lobe; RV, right ventricle; S, stomach.