Endothelial Rho kinase controls blood vessel integrity and angiogenesis.

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Molecular Biology

Background:

• Rho kinases 1 and 2 (ROCK1/2) are key regulators of actin cytoskeleton dynamics.
• ROCK1/2 are crucial for cardiovascular health and disease, with pharmacological inhibition showing benefits in various models.
• The specific role of endothelial ROCK signaling in vivo remains largely unknown.

Purpose of the Study:

• To investigate the consequences of endothelial cell-specific ROCK1 and ROCK2 deficiency in vivo.
• To elucidate the function of endothelial ROCK signaling in maintaining vascular integrity and angiogenesis.

Main Methods:

• Generated tamoxifen-inducible endothelial cell-specific ROCK1 and ROCK2 loss-of-function mouse models.
• Utilized cellular, biochemical, and molecular biology approaches to analyze vascular defects.
• Performed in vitro 3D endothelial sprouting assays to assess angiogenesis and lumen formation.

Main Results:

• Postnatal or adult loss of endothelial ROCK1/2 was lethal within a week due to multi-organ hemorrhage and loss of vascular integrity.
• Endothelial cells showed defective actin polymerization, impaired focal adhesion formation, and disrupted junctional integrity.
• Angiogenesis was perturbed, with defective actin polymerization, lumen formation, and cell polarization, particularly with ROCK2 deficiency.

Conclusions:

• Endothelial ROCK1 and ROCK2 are critical for maintaining vascular integrity, proper angiogenesis, and lumen formation.
• A single allele of ROCK2 is sufficient to maintain vascular growth and integrity in vivo.
• These findings necessitate careful consideration of ROCK inhibitor use in disease settings.