Myeloid GRK2 Regulates Obesity-Induced Endothelial Dysfunction by Modulating Inflammatory Responses in Perivascular Adipose Tissue

González-Amor, María; Vila-Bedmar, Rocío; Rodrigues-Díez, Raquel; Moreno-Carriles, Rosa; Arcones, Alba C.; Cruces-Sande, Marta; Salaices, Mercedes; Mayor, Federico; Briones, Ana M.; Murga, Cristina

doi:10.3390/antiox9100953

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Myeloid GRK2 Regulates Obesity-Induced Endothelial Dysfunction by Modulating Inflammatory Responses in Perivascular Adipose Tissue

María González-Amor

^1,2

Rocío Vila-Bedmar

^3,†

Raquel Rodrigues-Díez

^1,2,†

⁴,

^2,5,6,

^2,5,6,

^1,2

^2,5,6

^1,2,* and

^2,5,6,*

Departamento Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz, 28029 Madrid, Spain

Ciber de Enfermedades Cardiovasculares (CIBERCV), 28028 Madrid, Spain

Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos (URJC), 28022 Madrid, Spain

⁴

Servicio de Angiología y Cirugía Vascular, Hospital Universitario La Princesa, 28006 Madrid, Spain

⁵

Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (CBMSO) UAM-CSIC, 28049 Madrid, Spain

⁶

Instituto de Investigación Sanitaria, Hospital Universitario La Princesa, 28006 Madrid, Spain

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Antioxidants 2020, 9(10), 953; https://doi.org/10.3390/antiox9100953

Received: 18 September 2020 / Accepted: 30 September 2020 / Published: 4 October 2020

(This article belongs to the Special Issue Oxidative Stress in Obesity)

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Abstract

Perivascular adipose tissue (PVAT) is increasingly being regarded as an important endocrine organ that directly impacts vessel function, structure, and contractility in obesity-associated diseases. We uncover here a role for myeloid G protein-coupled receptor kinase 2 (GRK2) in the modulation of PVAT-dependent vasodilation responses. GRK2 expression positively correlates with myeloid- (CD68) and lymphoid-specific (CD3, CD4, and CD8) markers and with leptin in PVAT from patients with abdominal aortic aneurysms. Using mice hemizygous for GRK2 in the myeloid lineage (LysM-GRK2^+/−), we found that GRK2 deficiency in myeloid cells allows animals to preserve the endothelium-dependent acetylcholine or insulin-induced relaxation, which is otherwise impaired by PVAT, in arteries of animals fed a high fat diet (HFD). Downregulation of GRK2 in myeloid cells attenuates HFD-dependent infiltration of macrophages and T lymphocytes in PVAT, as well as the induction of tumor necrosis factor-α (TNFα) and NADPH oxidase (Nox)1 expression, whereas blocking TNFα or Nox pathways by pharmacological means can rescue the impaired vasodilator responses to insulin in arteries with PVAT from HFD-fed animals. Our results suggest that myeloid GRK2 could be a potential therapeutic target in the development of endothelial dysfunction induced by PVAT in the context of obesity. View Full-Text

Keywords: perivascular adipose tissue (PVAT); G protein-coupled receptor kinase 2 (GRK2); tumor necrosis factor-α (TNFα); NADPH oxidase (Nox); endothelial dysfunction

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MDPI and ACS Style

González-Amor, M.; Vila-Bedmar, R.; Rodrigues-Díez, R.; Moreno-Carriles, R.; Arcones, A.C.; Cruces-Sande, M.; Salaices, M.; Mayor, F., Jr.; Briones, A.M.; Murga, C. Myeloid GRK2 Regulates Obesity-Induced Endothelial Dysfunction by Modulating Inflammatory Responses in Perivascular Adipose Tissue. Antioxidants 2020, 9, 953. https://doi.org/10.3390/antiox9100953

AMA Style

González-Amor M, Vila-Bedmar R, Rodrigues-Díez R, Moreno-Carriles R, Arcones AC, Cruces-Sande M, Salaices M, Mayor F Jr., Briones AM, Murga C. Myeloid GRK2 Regulates Obesity-Induced Endothelial Dysfunction by Modulating Inflammatory Responses in Perivascular Adipose Tissue. Antioxidants. 2020; 9(10):953. https://doi.org/10.3390/antiox9100953

Chicago/Turabian Style

González-Amor, María, Rocío Vila-Bedmar, Raquel Rodrigues-Díez, Rosa Moreno-Carriles, Alba C. Arcones, Marta Cruces-Sande, Mercedes Salaices, Federico Mayor Jr., Ana M. Briones, and Cristina Murga. 2020. "Myeloid GRK2 Regulates Obesity-Induced Endothelial Dysfunction by Modulating Inflammatory Responses in Perivascular Adipose Tissue" Antioxidants 9, no. 10: 953. https://doi.org/10.3390/antiox9100953

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