Perivascular adipose tissue-derived leptin promotes vascular smooth muscle cell phenotypic switching via p38 mitogen-activated protein kinase in metabolic syndrome rats

Abstract

Perivascular adipose tissue (PVAT)-derived leptin is a detrimental adipocytokine and plays a critical role in the development of cardiovascular diseases in metabolic syndrome (MetS). During vascular remodeling, vascular smooth muscle cells (VSMCs) undergo phenotypic switching into a synthetic phenotype characterized by decreased expression of differentiation markers (smooth muscle myosin heavy chain, α-smooth muscle actin, and calponin) and increased proliferation. We aimed to determine whether PVAT-derived leptin influences VSMC phenotypic switching and to explore the underlying mechanisms in MetS rats. In vivo, 32 Wistar rats were divided into two groups that received either a normal diet (control rat) or a high-fat diet (MetS rats). After 16 weeks, rat aortas were stained using hematoxylin–eosin and imaged. VSMC differentiation markers and proliferating cell nuclear antigen (PCNA), PVAT-derived leptin, aortic leptin receptor (ObR), and p38 mitogen-activated protein kinase (MAPK) expression were detected. In vitro, aortic VSMCs were incubated with MetS rat PVAT conditioned medium (PVAT-CM) to mimic in vivo conditions and were pretreated with a p38 MAPK inhibitor (SB 203580) or leptin antagonist. Differentiation marker expression, including PCNA and p38 MAPK, was detected. MetS rats exhibited pronounced insulin resistance, hyperglycemia, hyperlipidemia, hypertension, obesity, and an associated increase in PVAT weight. VSMCs underwent phenotypic switching in MetS rat aorta and contributed to vascular remodeling. PVAT-derived leptin expression was higher in MetS rats than in control rats (P < 0.01). ObRa expression and p38 MAPK phosphorylation were upregulated in MetS rat aorta. In vitro, VSMCs incubated with MetS rat PVAT-CM underwent phenotypic switching, associated with increased p38 MAPK phosphorylation. This VSMC phenotypic switching was inhibited by pretreatment with SB 203580 or a leptin antagonist. These results suggest that in MetS rats, PVAT-derived leptin promotes VSMC phenotypic switching via a p38 MAPK-dependent pathway to exacerbate vascular remodeling.

Keywords

Perivascular adipose tissue leptin metabolic syndrome vascular smooth muscle cell phenotypic switching p38 mitogen-activated protein kinases

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