Endothelial Rho kinase controls blood vessel integrity and angiogenesis.

Area of Science:

• Cardiovascular Biology
• Cell Biology
• Molecular Biology

Background:

• Rho kinases 1 and 2 (ROCK1/2) are serine-threonine kinases regulating actin cytoskeleton dynamics.
• ROCK1/2 are expressed in cardiomyocytes, smooth muscle cells, and endothelial cells (ECs), influencing cardiovascular health and disease.
• Pharmacological ROCK inhibition shows benefits in various cardiovascular disease models, but endothelial ROCK signaling deficiency effects were unknown.

Purpose of the Study:

• To investigate the in vivo consequences of endothelial ROCK1 and ROCK2 signaling deficiency.
• To elucidate the roles of ROCK1 and ROCK2 in maintaining vascular integrity, angiogenesis, and lumen formation.

Main Methods:

• Generated tamoxifen-inducible endothelial-specific ROCK1/2 loss-of-function mouse models.
• Utilized cellular, biochemical, and molecular biology approaches to analyze survival and vascular defects.
• Performed 3D endothelial sprouting assays to assess angiogenesis and lumenization.

Main Results:

• Postnatal loss of endothelial ROCK1/2 was lethal within a week, causing multi-organ hemorrhage and vascular integrity loss.
• ECs showed deficient actin polymerization, impaired focal adhesion, and disrupted junctional integrity.
• ROCK2 deficiency, but not ROCK1, significantly impaired endothelial sprouting, lumenization, and cell polarization, correlating with ROCK2 substrate specificity.

Conclusions:

• Endothelial ROCK1 and 2 are essential for maintaining junctional integrity, proper angiogenesis, and lumen formation.
• A single allele of ROCK2 is sufficient to maintain vascular growth and integrity.
• Caution is warranted when using ROCK inhibitors in disease settings due to their critical role in endothelial function.