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Published on: February 23, 2020
PROGRESSION OF VASCULAR FUNCTION AND BLOOD PRESSURE IN A MOUSE MODEL OF KAWASAKI DISEASE
Insights
Kawasaki disease (KD) in mice shows vascular dysfunction linked to inflammation and oxidative stress. This dysfunction involves nitric oxide, reactive oxygen species, and cyclooxygenase (COX) pathways, highlighting potential therapeutic targets.
Area of Science:
- Cardiovascular Research
- Pediatric Vasculitis
- Immunology
Background:
- Kawasaki disease (KD) is a childhood vasculitis with potential long-term cardiovascular risks.
- The underlying vascular mechanisms contributing to cardiovascular complications in KD remain incompletely understood.
- Investigating a murine model is crucial for elucidating KD's vascular pathophysiology.
Purpose of the Study:
- To investigate vascular function and blood pressure in a murine model of Kawasaki disease.
- To explore the role of nitric oxide (NO), reactive oxygen species (ROS), and cyclooxygenase (COX) pathways in KD-induced vascular dysfunction.
- To examine the involvement of vascular smooth muscle cells and Toll-like receptor 4 (TLR4) in KD pathogenesis.
Main Methods:
- A murine model of KD was induced using the Candida albicans water-soluble (CAWS) fraction.
- Vascular function was assessed in aortic rings through contractility studies.
- In vitro studies utilized rat aortic smooth muscle cells to investigate molecular mechanisms, including COX2 expression and TLR4 signaling.
Main Results:
- The CAWS model induced significant vasculitis and elevated inflammatory markers in C28 mice.
- Vascular dysfunction, characterized by increased norepinephrine-induced contractility, was observed in CAWS-treated mice (C7 and C28).
- This dysfunction was mitigated by blocking NO, ROS, and COX-derived products, with increased COX2 expression in aortic smooth muscle cells via TLR4.
Conclusions:
- The murine KD model exhibits vascular dysfunction associated with COX-derived products, oxidant properties, and NO bioavailability.
- Vascular smooth muscle cells play a key role in KD-related vascular dysfunction and vasculitis through the TLR4 pathway.
- The CAWS model may not be suitable for studying KD-associated shock, and further research is needed on the role of vascular dysfunction and COXs in vasculitis.
Abstract:
Kawasaki disease (KD) is a systemic vasculitis of childhood characterized by vascular damage in the acute stage, which can persist into the late stage. The vascular mechanisms in the cardiovascular risk of KD are not fully studied. We investigated the vascular function and blood pressure in a murine model of KD. We used the Candida albicans water-soluble (CAWS) fraction model. Mice were injected with 4 mg CAWS for 5 consecutive days and separated into three groups. Control, CAWS 7 days (C7), and CAWS 28 days (C28). Hearts and arteries were harvested for vascular characterization. Rat aortic smooth muscle cells were used to studies in vitro. C7 presented elevated inflammatory markers in the coronary area and abdominal aortas, whereas C28 showed severe vasculitis. No difference was found in blood pressure parameters. Vascular dysfunction characterized by higher contractility to norepinephrine in C7 and C28 in aortic rings was abolished by blocking nitric oxide (NO), reactive oxygen species, and cyclooxygenase (COX)-derived products. The CAWS complex increased COX2 expression in rat aortic smooth muscle cells, which was prevented by Toll-like receptor 4 antagonist. Our data indicate that the murine model of KD is associated with vascular dysfunction likely dependent on COX-derived products, oxidant properties, and NO bioavailability. Furthermore, vascular smooth muscle cell may present an important role in the genesis of vascular dysfunction and vasculitis via the Toll-like receptor 4 pathway. Finally, the CAWS model seems not to be appropriate to study KD-associated shock. More studies are necessary to understand whether vascular dysfunction and COXs are triggers for vasculitis.
