Endotheliopathy of Obesity (original) (raw)

. Author manuscript; available in PMC: 2021 Jul 28.

Overview.

A virtuous cycle of endothelial and metabolic health is disrupted in obesity. Diet- induced obesity engenders dyslipidemia, insulin resistance, and hypertension, each of which impairs endothelial function. Conversely, accumulating data indicate that impaired endothelial function may lead to insulin resistance, hypertension, dyslipidemia, and obesity. Thus, dysfunction of the endothelium, i.e. an endotheliopathy, may beget metabolic as well as cardiovascular diseases.

The endothelium as mediator of cardiovascular health.

The endothelium is a monolayer of cells that comprises the luminal surface of all blood and lymphatic vessels. Interposed between the flowing blood or lymph, the endothelium regulates the interaction of the vessel wall with circulating cells, platelets, exosomes and humoral factors. Endothelial adhesion molecules and chemokines facilitate leukocyte traffic into tissues. A panoply of endothelial paracrine factors modulates the tone and growth of the underlying vascular smooth muscle. Paradigmatic of these paracrine factors is endothelium-derived nitric oxide (NO), a potent vasodilator that also suppresses proliferation of vascular smooth muscle cells and infiltration of leukocytes1. The generation of NO is also essential for endothelial cell proliferation and migration and critical for angiogenesis.

Endothelial dysfunction in obesity and metabolic disorders.

Endothelial vasodilator function (an indirect measure of NO generation by the endothelium) becomes impaired early in healthy adults upon onset of a high fat diet2. Individuals with dyslipidemia, insulin resistance, hypertension and other cardiovascular risk factors have endothelial vasodilator dysfunction. It is generally accepted that impairment of endothelial function by cardiovascular risk factors initiates the process of atherogenesis, and that persistent endothelial dysfunction contributes to progression of atherosclerosis and major adverse cardiovascular events3. Thus, atherosclerosis begins and ends with endothelial dysfunction: from the first day that endothelial adhesion molecules facilitate monocyte entry into the intima, to the day that the endothelium overlying the atherosclerotic plaque ulcerates, and vascular thrombosis ensues. Fortunately, endothelial dysfunction is reversible with successful treatment of cardiovascular risk factors. Normalization of endothelial function restores vascular homeostasis, reducing symptoms of coronary and peripheral arterial disease, and preventing myocardial infarction and stroke.

Endothelial dysfunction as a cause of Metabolic Disorders.

In the conceptual framework described above, the endothelium is the stage on which the cardiovascular risk factors play their role. But emerging evidence indicates that the endothelium itself may orchestrate metabolic disorders. In this regard, NO promotes insulin-mediated glucose disposal as well as perfusion in insulin-sensitive tissues (i.e. skeletal muscle, liver and adipose tissue)4. Pre-clinical studies revealed that deficiency of either endothelial or neuronal NO synthase causes insulin resistance and hypertension5. Genetic disruption of NO synthesis may induce insulin resistance by reducing microvascular recruitment and/or muscle glucose uptake in response to insulin, and/or by impairing hepatic glycogen synthesis. As such, it is intriguing that insulin resistance and Type II diabetes mellitus in humans are associated with increased levels of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA)6,7. By contrast, mice that have genetically reduced levels of ADMA are insulin sensitive8 and have greater angiogenic capacity9. Unsurprisingly, animals that generate more NO are both more insulin sensitive (NO improves perfusion of insulin sensitive tissues) and have greater angiogenic capacity (NO promotes endothelial cell proliferation and migration). However, is it possible that greater angiogenic capacity directly controls insulin sensitivity? In this issue of Circulation, Dr. Chen and her group at City of Hope make a compelling case for a more direct control of obesity and insulin sensitivity by the endothelium10.

Suppression of endothelial AGO1 promotes adipose vascularity and improves metabolic function.

As obesity develops, there is a decline in adipose tissue vascularity (which seems counterintuitive) and an increase in fibrosis. The authors speculated that the reduction in vascularity might have an adverse effect on adipose tissue function. Previously, these authors have shown that suppression of endothelial Argonaute 1 (AGO1; a key component of microRNA- induced silencing complex) promotes hypoxia-induced angiogenesis11. In the current study, they assessed the functional importance of AGO1-regulated endothelial function in vivo and its relevance to adipose tissue function and obesity. To begin, the group generated an endothelial specific knockout of AGO1 (KO). Subsequently, these mice and their wild-type littermates (WT) were given normal chow or a high-fat, high-sugar (HFHS) diet. No differences were observed between the groups when given a normal diet. When the animals were given a HFHS diet, the WT animals gained excess weight and became insulin resistant. By contrast, the KO mice did not gain excess weight, and they remained sensitive to insulin. In comparison to the WT mice fed a HFHS diet, KO mice had lower white and brown fat stores (by 30–50%) and lower liver weight (by 20%). Molecular markers of insulin sensitivity (Akt and AMPK phosphorylation) were increased in the adipocytes of EC AGO1-KO mice.

Intriguingly, there were no differences between the KO and WT mice in water or food consumption, or dietary fat absorption. Instead, KO mice seemed to have a higher catabolic rate, with higher oxygen consumption, carbon dioxide generation, and energy expenditure in both light and dark cycles. This difference was likely due to the fact that the KO mice exhibited “browning” of their subcutaneous fat, with smaller but more numerous adipocytes, and an increase in vascularity. Furthermore, there was increased expression of proteins involved in thermogenesis including uncoupling protein (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Transcriptional profiling of the subcutaneous fat revealed upregulation of the genetic components of pathways involved in angiogenesis, lipolysis, and mitochondrial function, consistent with greater adipose vascularity as well as insulin sensitivity.

Sequencing of AGO1-associated RNA transcripts in human endothelial cells revealed that thrombospondin (TSP1) is strongly downregulated in the EC AGO1 KO animals. Since TSP1 has anti-angiogenic activity, the suppression of TSP1 could contribute to the increased adipose vascularity in the KO animals. In confirmation of this finding, TSP1 levels were reduced in endothelial cells and adipocytes of brown and subcutaneous fat of the KO animals. Notably, angiogenic genes were enhanced and pro-inflammatory genes were reduced, in the EC from subcutaneous fat of the KO animals. Furthermore, systemic or local overexpression of TSP-1 in the subcutaneous fat reversed much of the functional, histological and molecular benefits of the endothelial AGO1 knockout. These studies suggested that much of the effect of the KO was due to TSP1 suppression, with a resultant increase in adipose angiogenesis. In this regard, NO is known to suppress TSP1 expression, and TSP1 levels are higher in animals deficient of endothelial NO synthase12.

To determine the clinical significance of the AGO1-TSP1 pathway in human vasculature, Tang and colleagues isolated the intima from mesenteric arteries of post-mortem tissues of obese patients or those with Type 2 diabetes mellitus, comparing these samples with those from patients without these two conditions. Intriguingly, they found that AGO1 and TSP1 expression was increased in the intima from diabetic or obese subjects. These data are consistent with the hypothesis that upregulation of an anti-angiogenic pathway promotes obesity and diabetes, although a causal association in humans remains to be demonstrated.

The endothelium as maestro of metabolism.

The work of Dr. Chen’s group reveals that the endothelium can directly regulate obesity and insulin resistance. By promoting an angiogenic program within endothelial cells, the vascularity of the adipose tissue was maintained in the EC AGO1-KO mice despite a high fat, high sucrose diet. Furthermore, the animals remained lean and insulin sensitive, due in part to a higher catabolic state.

There remain some intriguing scientific questions. Is the effect of the EC AGO1-KO entirely due to angiogenesis and improvement in perfusion of the adipose tissue? Or does the endothelium in the KO animals affect adipose tissue by secretion of paracrine factors or exosomes that modulate adipocyte function? Indeed, recent work from the Scherer group has clearly shown that endothelial cells transfer biological information to adipocytes via caveolin-1 containing exosomes13. In this case, it is possible that the endothelium in the KO animals secretes factors that affects adipose tissue, or even other organs (such as the liver), to influence the metabolic state. Another unanswered question regards the reduction in vascularity in obesity. Is the vascular rarefaction in adipose tissue simply due to an anti-angiogenic effect, e.g. mediated by TSP-1? It is also possible that the loss of the angiogenic program and acquisition of a pro-inflammatory transcriptome triggers an endothelial-to-mesenchyme transition that is responsible for the loss of vascularity and increase in fibrosis observed in adipose tissue from obese individuals. Indeed, inflammatory signaling is known to have global effects on the epigenome that increase DNA accessibility and cellular fluidity14. Such cellular fluidity could facilitate EndoMT in adipose tissue, which would explain the reduction in vascularity and increase in fibrosis. Finally, there are other conditions that are known to induce endothelial dysfunction (mental stress, senescence)15 that are also known to induce insulin resistance…..does endotheliopathy underlie the metabolic disorder in these cases?

In any event, this seminal work suggests a novel therapeutic avenue for the treatment of metabolic disorders. Indeed, TSP-1 appears to be an interesting target for therapeutic modulation for diabetes mellitus. In this regard, it is intriguing that the EC AGO1-KO mice had reduced liver weight, in addition to less adiposity. This effect was likely due to a reduction in hepatic steatosis. Thus, TSP-1 may also represent a new target in the treatment of non-alcoholic steatohepatitis (NASH). Fatty liver disease is becoming a worrisome epidemic as it can lead to cirrhosis and hepatic cancer. And of course, metabolic dysfunction is associated with cardiovascular disease, which remains the major cause of morbidity and mortality globally. Thus, new paradigm-shifting work like that of Tang and colleagues is welcome news.

Conflict of Interest Disclosures.

Dr. Cooke is on the Scientific Advisory Board of Humann Inc, which makes products related to nitric oxide and cardiovascular health; is an inventor on multiple patents assigned to Stanford University or Houston Methodist Hospital related to endothelial function and regeneration; and has been a collaborator and co-author with Dr. Zhen Chen. This work was supported by National Institutes of Health (R01 grants HL133254 and HL148338).

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