ZFIN ID: ZDB-PUB-170916-7
Cavin-2 regulates the activity and stability of endothelial nitric oxide synthase (eNOS) in angiogenesis
Boopathy, G.T.K., Kulkarni, M., Ho, S.Y., Boey, A., Chua, E.W.M., Barathi, V.A., Carney, T.J., Wang, X., Hong, W.
Date: 2017
Source: The Journal of biological chemistry   292(43): 17760-17776 (Journal)
Registered Authors: Carney, Tom
Keywords: angiogenesis, cell biology, eNOS, nitric oxide, nitric oxide synthase, signal transduction, zebrafish
MeSH Terms:
  • Animals
  • Disease Models, Animal
  • Enzyme Stability
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Mice
  • Nitric Oxide/genetics
  • Nitric Oxide/metabolism
  • Nitric Oxide Synthase Type III/genetics
  • Nitric Oxide Synthase Type III/metabolism*
  • Retinal Neovascularization/genetics
  • Retinal Neovascularization/metabolism*
  • Retinopathy of Prematurity/genetics
  • Retinopathy of Prematurity/metabolism*
  • Retinopathy of Prematurity/pathology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 28912276 Full text @ J. Biol. Chem.
Angiogenesis is a highly regulated process for formation of new blood vessels from pre-existing ones. Angiogenesis is dysregulated in various pathologies, including age-related macular degeneration, arthritis, and cancer. Inhibiting pathological angiogenesis therefore represents a promising therapeutic strategy for treating these disorders, highlighting the need to study angiogenesis in more detail. To this end, identifying the genes essential for blood vessel formation and elucidating their function are crucial for a complete understanding of angiogenesis. Here, focusing on potential candidate genes for angiogenesis, we performed a morpholino-based genetic screen in zebrafish and identified Cavin-2, a membrane-bound phosphatidylserine-binding protein and critical organizer of caveolae (small microdomains in the plasma membrane), as a regulator of angiogenesis. Using endothelial cells, we show that Cavin-2 is required for in vitro angiogenesis and also for endothelial cell proliferation, migration, and invasion. We noted a high level of Cavin-2 expression in the neovascular tufts in the mouse model of oxygen-induced retinopathy, suggesting a role for Cavin-2 in pathogenic angiogenesis. Interestingly, we also found that Cavin-2 regulates the production of nitric oxide (NO) in endothelial cells by controlling the stability and activity of the endothelial nitric-oxide synthase (eNOS) and that Cavin-2 knockdown cells produce much less NO than WT cells. Also, mass spectrometry, flow cytometry, and electron microscopy analyses indicated that Cavin-2 is secreted in endothelial microparticles (EMPs) and is required for EMP biogenesis. Taken together, our results indicate that in addition to its function in caveolae biogenesis, Cavin-2 plays a critical role in endothelial cell maintenance and function by regulating eNOS activity.