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

• Main Authors: María González-Amor, Rocío Vila-Bedmar, Raquel Rodrigues-Díez, Rosa Moreno-Carriles, Alba C. Arcones, Marta Cruces-Sande, Mercedes Salaices, Federico Mayor, Ana M. Briones, Cristina Murga
• Format: Article
• Language: English
• Published: MDPI AG 2020-10-01
• Series: Antioxidants
• Subjects: perivascular adipose tissue (PVAT); G protein-coupled receptor kinase 2 (GRK2); tumor necrosis factor-α (TNFα); NADPH oxidase (Nox); endothelial dysfunction
• Online Access: https://www.mdpi.com/2076-3921/9/10/953

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 <b>(</b>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.