Vascular Kinin B 1 and B 2 Receptors Determine Endothelial Dysfunction through Neuronal Nitric Oxide Synthase

• Published in: Frontiers in physiology Vol. 8; p. 228
• Main Authors: Mesquita, Thássio R R, Campos-Mota, Gianne P, Lemos, Virgínia S, Cruz, Jader S, de Jesus, Itamar C G, Camargo, Enilton A, Pesquero, Jorge L, Pesquero, João B, Capettini, Luciano Dos Santos A, Lauton-Santos, Sandra
• Format: Journal Article
• Language: English
• Published: Switzerland 28-04-2017
• Subjects: kinin receptors; nitric oxide synthases; nitric oxide; vasorelaxation; endothelial dysfunction; reactive oxygen species
• ISSN: 1664-042X; 1664-042X
• DOI: 10.3389/fphys.2017.00228

B
- and B
-kinin receptors are G protein-coupled receptors that play an important role in the vascular function. Therefore, the present study was designed to evaluate the participation of kinin receptors in the acetylcholine (ACh)-induced vascular relaxation, focusing on the protein-protein interaction involving kinin receptors with endothelial and neuronal nitric oxide synthases (eNOS and nNOS). Vascular reactivity, nitric oxide (NO·) and reactive oxygen species (ROS) generation, co-immunoprecipitation were assessed in thoracic aorta from male wild-type (WT), B
- (B
R
), B
- (B
R
) knockout mice. Some vascular reactivity experiments were also performed in a double kinin receptors knockout mice (B
B
R
). For pharmacological studies, selective B
- and B
-kinin receptors antagonists, NOS inhibitors and superoxide dismutase (SOD) mimetic were used. First, we show that B
- and B
-kinin receptors form heteromers with nNOS and eNOS in thoracic aorta. To investigate the functionality of these protein-protein interactions, we took advantage of pharmacological tools and knockout mice. Importantly, our results show that kinin receptors regulate ACh-induced relaxation via nNOS signaling in thoracic aorta with no changes in NO· donor-induced relaxation. Interestingly, B
B
R
presented similar level of vascular dysfunction as found in B
R
or B
R
mice. In accordance, aortic rings from B
R
or B
R
mice exhibit decreased NO· bioavailability and increased superoxide generation compared to WT mice, suggesting the involvement of excessive ROS generation in the endothelial dysfunction of B
R
and B
R
mice. Alongside, we show that impaired endothelial vasorelaxation induced by ACh in B
R
or B
R
mice was rescued by the SOD mimetic compound. Taken together, our findings show that B
- and B
-kinin receptors regulate the endothelium-dependent vasodilation of ACh through nNOS activity and indicate that molecular disturbance of short-range interaction between B
- and B
-kinin receptors with nNOS might be involved in the oxidative pathogenesis of endothelial dysfunction.