Uncoupling caveolae from intracellular signaling in vivo
Circulation research, 2016•Am Heart Assoc
Rationale: Caveolin-1 (Cav-1) negatively regulates endothelial nitric oxide (NO) synthase–
derived NO production, and this has been mapped to several residues on Cav-1, including
F92. Herein, we reasoned that endothelial expression of an F92ACav-1 transgene would let
us decipher the mechanisms and relationships between caveolae structure and intracellular
signaling. Objective: This study was designed to separate caveolae formation from its
downstream signaling effects. Methods and Results: An endothelial-specific doxycycline …
derived NO production, and this has been mapped to several residues on Cav-1, including
F92. Herein, we reasoned that endothelial expression of an F92ACav-1 transgene would let
us decipher the mechanisms and relationships between caveolae structure and intracellular
signaling. Objective: This study was designed to separate caveolae formation from its
downstream signaling effects. Methods and Results: An endothelial-specific doxycycline …
Rationale:
Caveolin-1 (Cav-1) negatively regulates endothelial nitric oxide (NO) synthase–derived NO production, and this has been mapped to several residues on Cav-1, including F92. Herein, we reasoned that endothelial expression of an F92ACav-1 transgene would let us decipher the mechanisms and relationships between caveolae structure and intracellular signaling.
Objective:
This study was designed to separate caveolae formation from its downstream signaling effects.
Methods and Results:
An endothelial-specific doxycycline-regulated mouse model for the expression of Cav-1-F92A was developed. Blood pressure by telemetry and nitric oxide bioavailability by electron paramagnetic resonance and phosphorylation of vasodilator–stimulated phosphoprotein were determined. Caveolae integrity in the presence of Cav-1-F92A was measured by stabilization of caveolin-2, sucrose gradient, and electron microscopy. Histological analysis of heart and lung, echocardiography, and signaling were performed.
Conclusions:
This study shows that mutant Cav-1-F92A forms caveolae structures similar to WT but leads to increases in NO bioavailability in vivo, thereby demonstrating that caveolae formation and downstream signaling events occur through independent mechanisms.
Am Heart Assoc