Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish
Bin Ren, … , Randall T. Peterson, Michael Simons
Bin Ren, … , Randall T. Peterson, Michael Simons
Published March 8, 2010
Citation Information: J Clin Invest. 2010;120(4):1217-1228. https://doi.org/10.1172/JCI39837.
View: Text | PDF
Research Article Vascular biology

ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish

  • Text
  • PDF
Abstract

Arterial morphogenesis is an important and poorly understood process. In particular, the signaling events controlling arterial formation have not been established. We evaluated whether alterations in the balance between ERK1/2 and PI3K signaling pathways could stimulate arterial formation in the setting of defective arterial morphogenesis in mice and zebrafish. Increased ERK1/2 activity in mouse ECs with reduced VEGF responsiveness was achieved in vitro and in vivo by downregulating PI3K activity, suppressing Akt1 but not Akt2 expression, or introducing a constitutively active ERK1/2 construct. Such restoration of ERK1/2 activation was sufficient to restore impaired arterial development and branching morphogenesis in synectin-deficient mice and synectin-knockdown zebrafish. The same approach effectively stimulated arterial growth in adult mice, restoring arteriogenesis in mice lacking synectin and in atherosclerotic mice lacking both LDL-R and ApoB48. We therefore conclude that PI3K-ERK1/2 crosstalk plays a key role in the regulation of arterial growth and that the augmentation of ERK signaling via suppression of the PI3K signaling pathway can effectively stimulate arteriogenesis.

Authors

Bin Ren, Yong Deng, Arpita Mukhopadhyay, Anthony A. Lanahan, Zhen W. Zhuang, Karen L. Moodie, Mary Jo Mulligan-Kehoe, Tatiana V. Byzova, Randall T. Peterson, Michael Simons

×

Figure 3

Functional effects of partial PI3K inhibition in synectin-deficient AECs.

Options: View larger image (or click on image) Download as PowerPoint
Functional effects of partial PI3K inhibition in synectin-deficient AECs...
(A) Cell migration was assessed in the modified Boyden chamber assay. Synectin-deficient AECs were exposed to vehicle, 25 ng/ml VEGF-A165, 4 μM GS4898, a combination of VEGF and GS4898, or a combination of GS4898 and VEGF in the presence of 10 μM U0126. WT AECs were treated with either vehicle or VEGF-A165. The extent of migration is expressed as a ratio relative to vehicle-treated synectin-deficient AECs. Note full restoration of migration of synectin-deficient AECs exposed to GS4898 in the presence of VEGF. (B) 3D collagen tube branching assay. Synectin-deficient and WT AECs were placed in 3D collagen in the presence of 25 ng/ml VEGF, 4 μM GS4898, or both. The extent of branching was assessed 24 hours later and expressed as fold change relative to untreated control synectin-deficient AECs. Note restoration of branching in synectin-deficient AECs by GS4898 treatment. (C and D) In vitro Matrigel. The extent of cords branching was assessed in synectin-deficient AECs placed on growth factor–depleted Matrigel and exposed to 25 ng/ml VEGF-A165, 4 μM GS4898, a combination of VEGF and GS4898, or a combination of GS4898 and VEGF in the presence of 10 μM U0126. WT AECs exposed to VEGF were used as a control. All results are expressed relative to untreated control synectin-deficient AECs. Note restoration of branching in synectin-deficient AECs by GS4898 treatment. *P < 0.05, **P < 0.001 vs. control. Scale bars: 500 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts