Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art. Sprouting angiogenesis—a process by which new blood vessels grow from existing ones—is an ubiquitous phenomenon in health and disease of higher organisms, playing a crucial role in organogenesis, wound healing, inflammation, as well as on the onset and progression of over 50 different diseases such as cancer, rheumatoid arthritis and diabetes. Mathematical models have the ability to suggest relevant hypotheses with respect to the mechanisms of cell movement and rearrangement within growing vessel sprouts. The inclusion of both biochemical and mechanical processes in a mathematical model of sprouting angiogenesis permits to describe sprout extension as a function of the forces exerted by the cells in the tissue. It also allows to question the regulation of biochemical processes by mechanical forces and vice-versa. In this work we present a compact model of sprouting angiogenesis that includes the mechanical characteristics of the vessel and the tissue. We use this model to suggest the mechanism for the regulation of proliferation within sprout formation. We conclude that the tip cell has the role of creating a tension in the cells that follow its lead. On those first cells of the stalk, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. The modelling strategy used, deemed phase-field, permits to describe the evolution of the shape of different domains in complex systems. It is focused on the movement of the interfaces between the domains, and not on an exhaustive description of the transport properties within each domain. For this reason, it requires a reduced number of parameters, and has been used extensively in modelling other biological phenomena such as tumor growth. The coupling of mechanical and biochemical processes in a compact mathematical model of angiogenesis will enable the study of lumen formation and aneurisms in the near future. Also, this framework will allow the study of the action of flow in vessel remodelling, since local forces can readily be coupled with cell movement to obtain the final vessel morphology.

Background and objectives: The therapeutic effects of the dopamine D2 receptor (D2R) agonist, bromocriptine, in type 2 diabetes (T2D) have been attributed to central nervous system actions. However, peripheral dopamine directly modulates glucose uptake in insulin-sensitive tissues and lipid metabolism in adipose tissue (AT). We hypothesized that the dopaminergic system may be impaired in the adipose tissue of patients with T2D and that the therapeutic actions of bromocriptine could involve the modulation of metabolism in this tissue. Methods: The expression of dopamine receptors was evaluated in visceral AT samples from patients with obesity and stratified in several groups: insulin sensitive (IS); insulin resistance (IR) normoglycaemic; insulin resistant prediabetic; insulin resistant diabetic, according to Ox-HOMA2IR, fasting glycaemia and HbA1c levels. T2D Goto-Kakizaki rats (GK) were fed a high-caloric diet (HCD) for five months and treated with bromocriptine (10 mg/kg/day, i.p.) in the last month. The levels of dopaminergic system mediators and markers of insulin sensitivity and glucose and lipid metabolism were assessed in the peri-epididymal adipose tissue (pEWAT) and brown (BAT) adipose tissues, liver, and skeletal muscle. Results: Patients with IR presented a decreasing trend of DRD1 expression in the visceral adipose tissue, being correlated with the expression of UCP1, PPARA, and insulin receptor (INSR) independently of insulin resistance and body mass index. Although no differences were observed in DRD2, DRD4 expression was significantly decreased in patients with prediabetes and T2D. In HCD-fed diabetic rats, bromocriptine increased D1R and tyrosine hydroxylase (TH) levels in pEWAT and the liver. Besides reducing adiposity, bromocriptine restored GLUT4 and PPARγ levels in pEWAT, as well as postprandial InsR activation and postabsorptive activation of lipid oxidation pathways. A reduction of liver fat, GLUT2 levels and postprandial InsR and AMPK activation in the liver was observed. Increased insulin sensitivity and GLUT4 levels in BAT and an improvement of the overall metabolic status were observed. Conclusions: Bromocriptine treatment remodels adipose tissue and the liver dopaminergic system, with increased D1R and TH levels, resulting in higher insulin sensitivity and catabolic function. Such effects may be involved in bromocriptine therapeutic effects, given the impaired expression of dopamine receptors in the visceral adipose tissue of IR patients, as well as the correlation of D1R expression with InsR and metabolic mediators.

Context:Adipose tissue is one of the first organs to develop insulin resistance even with moderate BMI. However, the contribution of developing hyperglycaemia and concomitant methylglyoxal increment to tissue dysfunction during type 2 diabetes progression was not addressed before. Methods:Young and aged Wistar and Goto-Kakizaki rats (non-obese model of type 2 diabetes) and a group of MG-treated W rats were used to investigate the chronic effects of hyperglycaemia and ageing and specifically MG-induced mechanisms. Results:Diabetic and aged rats showed decreased adipose tissue irrigation and interstitial hypoxia. Hyperglycaemia of diabetic rats leaded to fibrosis and accumulation of PAS-positive components, exacerbated in aged animals, which also showed decreased hipoadiponectinemia, increased MCP-1 expression and macrophage infiltration to glycated fibrotic regions. MG leaded to increased free fatty acids, hipoadiponectinemia, decreased irrigation, hypoxia and macrophage recruitment for glycated fibrotic regions. Conclusions:MG contributes to dysfunction of adipose tissue during type 2 diabetes progression.

Microvascular dysfunction has been suggested to trigger adipose tissue dysfunction in obesity. This study investigates the hypothesis that glycation impairs microvascular architecture and expandability with an impact on insulin signalling. Animal models supplemented with methylglyoxal (MG), maintained with a high-fat diet (HFD) or both (HFDMG) were studied for periepididymal adipose (pEAT) tissue hypoxia and local and systemic insulin resistance. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantify blood flow in vivo, showing MG-induced reduction of pEAT blood flow. Increased adipocyte size and leptin secretion were observed only in rats feeding the high-fat diet, without the development of hypoxia. In turn, hypoxia was only observed when MG was combined (HFDMG group), being associated with impaired activation of the insulin receptor (Tyr1163), glucose intolerance and systemic and muscle insulin resistance. Accordingly, the adipose tissue angiogenic assay has shown decreased capillarization after dose-dependent MG exposure and glyoxalase-1 inhibition. Thus, glycation impairs adipose tissue capillarization and blood flow, hampering its expandability during a high-fat diet challenge and leading to hypoxia and insulin resistance. Such events have systemic repercussions in glucose metabolism and may lead to the onset of unhealthy obesity and progression to type 2 diabetes.