Emerging Roles of Vascular Endothelium in Metabolic Homeostasis

Abstract

Our understanding of the role of the vascular endothelium has evolved over the past two decades, with the recognition that it is a dynamically regulated organ and that it plays a nodal role in a variety of physiological and pathological processes. Endothelial cells (ECs) are not only a barrier between the circulation and peripheral tissues, but also actively regulate vascular tone, blood flow and platelet function. Dysregulation of ECs contributes to pathological conditions such as vascular inflammation, atherosclerosis, hypertension, cardiomyopathy, retinopathy, neuropathy and cancer. The close anatomical relationship between vascular endothelium and highly vascularized metabolic organs/tissues suggests that the crosstalk between ECs and these organs is vital for both vascular and metabolic homeostasis. Numerous reports support that hyperlipidemia, hyperglycemia and other metabolic stresses result in endothelial dysfunction and vascular complications. However, how ECs may regulate metabolic homeostasis remains poorly understood. Emerging data suggest that the vascular endothelium plays an unexpected role in the regulation of metabolic homeostasis and that endothelial dysregulation directly contributes to the development of metabolic disorders. Here, we review recent studies about the pivotal role of ECs in glucose and lipid homeostasis. In particular, we introduce the concept that the endothelium adjusts its barrier function to control the trans-endothelial transport of fatty acids, lipoproteins, lipoprotein lipases, glucose and insulin. In addition, we summarize reports that ECs communicate with metabolic cells through EC-secreted factors and we discuss how endothelial dysregulation contributes directly to the development of obesity, insulin resistance, dyslipidemia, diabetes, cognitive defects and fatty liver disease.

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

“…Nevertheless, in our patient, we cannot exclude that insulin resistant diabetes could also contribute to endothelial dysfunction, leading to atherosclerosis, as previously suggested in patients with FPLD2 due to LMNA p.Arg482 "hotspot" variants [5]. However, the inverse relationship could also be discussed since it was recently shown that endothelial dysfunction, through secreted factors, may directly alter adipose tissue homeostasis and lead to insulin resistance [54]. Direct evidence that endothelial cell senescence induces adipose tissue metabolic dysfunction and systemic insulin resistance was recently demonstrated in Tie2-TERF2DN-Tg mice, which display an endothelium-specific form of progeria [55].…”

Loss of Bone Morphogenetic Protein-binding Endothelial Regulator Causes Insulin Resistance

“…Inflammation is not observed in BMPER iKO mice. Given that vascular inflammation also disrupts function of metabolic tissues such as liver and WAT [18][19][20] , we examined whether BMPER depletion resulted in an inflammatory response in these tissues. In the liver of BMPER iKO and WT mice, the induction of the inflammatory cytokine IL1β ( Supplementary Fig.…”

The Vascular Involvement in Soft Tissue Fibrosis—Lessons Learned from Pathological Scarring

“…Fibrosis in the space of Disse is preceded by loss of LSEC differentiation that leads to the defenestration of the LSEC layer and the development of a subendothelial basement membrane: this process is known as capillarization [21,22]. This capillarization associates with the endothelial dysfunction of the LSECs [23,24]. Initially, the defenestration can still be reversed by removing hepatotoxin [25].…”