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

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

doi:10.3390/antiox9100953

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.

Highlights

Obesity is a very prevalent condition defined by increased adiposity and metabolic dysfunction that correlates in humans and animal models of disease with hypertension and vascular alterations, such as endothelial dysfunction or structural and mechanical alterations
We recently reported that a reduction of G protein-coupled receptor kinase 2 (GRK2) levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) by downregulating a pro-inflammatory macrophage profile [23]
perivascular adipose tissue (PVAT) is the major site for macrophage and T cell accumulation in human abdominal aortic aneurysm (AAA [24])

Summary

Introduction

Obesity is a very prevalent condition defined by increased adiposity and metabolic dysfunction that correlates in humans and animal models of disease with hypertension and vascular alterations, such as endothelial dysfunction or structural and mechanical alterations. Apart from the visceral and subcutaneous fat depots, numerous blood vessels are surrounded by a specific type of adipose tissue termed perivascular adipose tissue (PVAT). Increasing evidence demonstrates that PVAT acts as a secretory and endocrine organ with a direct impact on vessel function, structure, and contractility [3]. Other cell types, such as macrophages, lymphocytes, and fibroblasts, are found in PVAT and may contribute to its function. When compared with other adipose tissue depots, PVAT shows a distinct pattern of expression of pro-inflammatory and adipokine mediators and has particular morphological features [4]

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