Cardiovascular risk factors have an impact on the biology of pericytes

Abstract

Introduction

Pericytes are critical for capillary health and function; however, whether and how they may contribute to the pathophysiology of cardiovascular diseases is poorly known. Notably, while the detrimental effects of cardiovascular risk factors on endothelial cells have been extensively studied, little is known about their impact on the biology of pericytes.

Objective

Our aim was to investigate pericyte homeostasis in the heart and brain of adult mice, after they have been exposed to type 2 diabetes or depleted by 50%.

Method

In vivo, to deplete pericytes, we used Pdgfrb-Cre/ERT2; Rosa-DTA mice in which diphtheria toxin expression is specifically induced in mural cells after tamoxifen injections. Type 2 diabetes was induced in C57BL6/J mice by a high fat diet (HFD; 60% of fat) regimen combined with low dose-streptozotocin (STZ) injections. In vitro experiments were performed on primary cultured mouse cardiac pericytes isolated from 7–14 days-old pups.

Results

In diabetes, cardiac pericyte density is reduced by 20% in C57BL6/J mice, suggesting compromised pericyte survival or renewal/proliferation is compromised by diabetes. To investigate whether hyperlipidemia and/or hyperglycemia affect these processes, we conducted in vitro and in vivo assays using cultured cardiac pericytes and DTA mice. We first characterized pericyte renewal in normal conditions by depleting 50% of pericytes in mice. Pericyte regeneration in the heart starts on day 4 after depletion and is almost complete by day 21 (pericyte density = 91% of controls). Consistently, cell proliferation, measured by KI67 staining, was observed from day 4 to day 14 post-depletion. Interestingly, pericyte renewal kinetic seems to be organ-specific: brain pericyte regeneration is slower (71% of controls after 28 days). To test the effects of hyperlipidemia and hyperglycemia on proliferation, mice were fed a high-fat diet or treated with STZ before pericyte depletion. Neither condition impaired pericyte proliferation. In vitro, glucose, free fatty acids, or LDL did not affect BrdU incorporation in cultured pericytes. However, hyperlipidemia may reduce pericyte survival, as free fatty acids, notably palmitate and oleate, significantly increased necrosis in vitro.

Conclusion

This study indicates that pericytes can undergo extensive remodeling after a stress in adults. Cardiovascular risk factors, such as obesity and diabetes, may impair pericyte survival in the heart suggesting that these cells, known to be critical for microvascular integrity, could contribute to the onset of cardiac diseases.