Obesity Inhibits Angiogenesis Through TWIST1-SLIT2 Signaling.

Tendai Hunyenyiwa,Kienna Matus,Tadanori Mammoto,Priscilla Kyi,Akiko Mammoto,Kathryn Hendee

doi:10.3389/fcell.2021.693410

Tendai Hunyenyiwa, Kienna Matus + Show 4 more

Open Access

https://doi.org/10.3389/fcell.2021.693410

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Abstract

Angiogenesis is required for functional adipose tissue maintenance, remodeling, and expansion. Physiologically balanced adipogenesis and angiogenesis are inhibited in subcutaneous adipose tissue in obese humans. However, the mechanism by which angiogenesis is inhibited in obese adipose tissue is not fully understood. Transcription factor TWIST1 controls angiogenesis and vascular function. TWIST1 expression is lower in obese human adipose tissues. Here, we have demonstrated that angiogenesis is inhibited in endothelial cells (ECs) isolated from adipose tissues of obese humans through TWIST1-SLIT2 signaling. The levels of TWIST1 and SLIT2 are lower in ECs isolated from obese human adipose tissues compared to those from lean tissues. Knockdown of TWIST1 in lean human adipose ECs decreases, while overexpression of TWIST1 in obese adipose ECs restores SLIT2 expression. DNA synthesis and cell migration are inhibited in obese adipose ECs and the effects are restored by TWIST1 overexpression. Obese adipose ECs also inhibit blood vessel formation in the gel subcutaneously implanted in mice, while these effects are restored when gels are mixed with SLIT2 or supplemented with ECs overexpressing TWIST1. These findings suggest that obesity impairs adipose tissue angiogenesis through TWIST1-SLIT2 signaling.

Highlights

Obesity is regarded as a world epidemic with more than 1 billion people overweight in the world (Huang et al, 2016; GBD 2015 Mortality and Causes of Death Collaborators, 2016) and approximately two-thirds of US adults are overweight or obese (Cao, 2010)
We examined the effects of obesity on vascular formation using the mouse gel implantation system, in which fibrin gels supplemented with GFP-labeled lean (BMI < 30) vs. obese (BMI > 30) human adipose endothelial cells (ECs) were subcutaneously implanted on the back of the immunocompromised NOD SCID gamma (NSG) mice for 7 days (Supplementary Figure 2A; Mammoto et al, 2019c; Hendee et al, 2021)
We have used ECs isolated from lean vs. obese human subcutaneous adipose tissues and demonstrated that vascular formation is inhibited in obese ECs through TWIST1-SLIT2 signaling

Summary

INTRODUCTION

Obesity is regarded as a world epidemic with more than 1 billion people overweight in the world (Huang et al, 2016; GBD 2015 Mortality and Causes of Death Collaborators, 2016) and approximately two-thirds of US adults are overweight or obese (Cao, 2010). While healthy subcutaneous adipose tissue is maintained by physiologically balanced adipogenesis and angiogenesis, inflammatory and antiangiogenic signals in hypertrophic obese adipose tissues inhibit angiogenesis and disrupt physiological vascular function, which results in local hypoxia, metabolic stress, and tissue dysfunction (Hosogai et al, 2007; Halberg et al, 2009; Pasarica et al, 2009; Cao, 2010; Christiaens and Lijnen, 2010; Xiao et al, 2016; Crewe et al, 2017; Hammarstedt et al, 2018; Chouchani and Kajimura, 2019). Modulating TWIST1-SLIT2 signaling in ECs could be a novel therapeutic approach for obesity and obesity-associated diseases

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