Deletion of adipocyte NOS3 potentiates high-fat diet-induced hypertension and vascular remodelling via chemerin

Abstract

Aims Obesity is an epidemic that is a critical contributor to hypertension and other cardiovascular diseases. Current paradigms suggest that endothelial nitric oxide synthase (eNOS/NOS3) in the vessel wall is the primary regulator of vascular function and blood pressure. However, recent studies have revealed the presence of eNOS/NOS3 in the adipocytes of white adipose tissues and perivascular adipose tissues (PVATs). The current understanding of the role of adipocyte NOS3 is based mainly on studies using global knockout models. The present study aimed to elucidate the functional significance of adipocyte NOS3 for vascular function and blood pressure control. Methods and Results We generated an adipocyte-specific NOS3 knockout mouse line using adiponectin promotor-specific Cre-induced gene inactivation. Control and adipocyte-specific NOS3 knockout (A-NOS3 KO) mice were fed a high-fat diet (HFD). Despite less weight gain, A-NOS3 KO mice exhibited a significant increase in blood pressure after HFD feeding, associated with exacerbated vascular dysfunction and remodeling. A-NOS3 KO mice also showed increased expression of signature markers of inflammation and hypoxia in the PVATs. Among the differentially expressed adipokines, we have observed an upregulation of a novel adipokine, chemerin, in A-NOS3 KO mice. Chemerin was recently reported to link obesity and vascular dysfunction. Treatment with chemerin neutralizing antibody normalized the expression of remodeling markers in the aorta segments cultured in serum from HFD-fed A-NOS3 KO mice ex vivo. Conclusions These data suggest that NOS3 in adipocytes is vital in maintaining vascular homeostasis; dysfunction of adipocyte NOS3 contributes to obesity-induced vascular remodeling and hypertension.

Sex-Specific Effects of Cholesteryl Ester Transfer Protein (CETP) on the Perivascular Adipose Tissue

“… 38 , 39 The functional significance of the adipocyte eNOS for vascular function was recently elucidated. Man and colleagues 40 generated adipocyte-specific eNOS knockout mice and observed exacerbated vascular dysfunction and remodeling, as well as increased expression of inflammation markers in the PVAT.…”

Endothelial Nitric Oxide synthase (eNOS) in Preeclampsia: An Update

“…While eNOS is mainly expressed by endothelial cells [18,20], it is also detectable in cardiomyocytes [21], adipocytes [22], kidney tubular epithelial cells [23] and syncytiotrophoblasts of human placenta [24]. Normal eNOS function is essential for maintaining appropriate blood pressure (BP) through its enzymatic conversion of L-arginine to nitric oxide (NO)-a colorless gas with short half-life [25]-and cyclic guanosine monophosphate (cGMP) is the mediator of its biological function.…”

LOC646762 Is Involved in Adipogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells

“… 6 Adipocyte differentiation is regulated by expression of multiple functional genes, noncoding RNAs, transcription factors, hormones, and signaling pathway molecules and involves a series of biochemical reactions triggered by various hormones and cytokines. 7 Dysregulated adipocyte differentiation is closely related to several diseases such as obesity, 8 diabetes, 9 cardiovascular diseases, 10 and fatty liver; 11 however, its regulatory mechanism remains unclear. Thus, elucidating the regulatory mechanism of adipogenic differentiation is crucial for identifying new therapeutic targets for these diseases.…”