Obesity,blood rheology and angiogenesis

Obesity constitutes a serious public health problem. The results of epidemiological studies indicate that the worldwide incidence of obesity occurrence has almost doubled over the last three decades [1]. Obesity is an important risk factor for death and an increased morbidity of cardiovascular system diseases, diabetes and some cancers [2]. Apart from metabolic, hormonal or haemodynamic dysfunctions, the rheological properties of blood are more and more often being determined increasingly found to serve as a marker of pathological changes associated with obesity [3, 4].

The adipose tissue, especially the visceral adipose tissue, is responsible for the production of many paracrine and endocrine substances: FGF21, IL-6, IL-4, IL-7, IL-8, IL-15, LIF, IGF 1, IGF 2, and EPO [5]. These substances may affect the function of other organs and tissues in the human body through various complex mechanisms [6].

Adipose tissue is actively involved in angiogenesis through secretion of biologically active substances such as angiopoietin 2 [7], PDGFRβ [8], adiponectin, leptin, and VEGF [9].

Some of the most common and best-studied reactions of adipose tissue involving angiogenesis factors are the impact on the remodelling of particular vascular wall layers, the development of atherosclerosis, and the change of blood rheological properties [10].

The angiogenesis factors PDGFβ, TGFβ, TNFα, IL-1, IL-6, and IFNγ influence endothelial gene expression, causing changes in the endothelial cell adhesion profiles among obese people, initiation of the inflammatory response, disturbance of the immune system cell migration and consequently, promotion of atheromatous plaque development [11–13].

The influence of obesity on changes in blood rheological properties in obese people is well known and documented [14–16]. Blood and plasma viscosity are considered to be risk factors for atherosclerosis [17], while rheological disorders of blood have been shown to occur in hypertension and diabetes and are often associated with obesity [3, 19].

Changes in blood rheological properties may affect shear forces generated by blood flow, which constitute an important factor in determining endothelial function [20] and gene expression [21]. Laminar blood flow changes the pathway of signal transduction from the cell membrane to the nucleus and leads to increased production of proinflammatory factor NF-κB and other neoangiogenesis factors including TGF-beta. On the other hand, laminar blood flow promotes an antioxidant endothelial response and transcription of genes including the PPAR-gamma (Peroxisome proliferator-activated receptor gamma), which improves the structure of blood vessels. Low shear forces and turbulent flow may result in thrombosis and inflammatory reactions [22]. It has also been proven that the regions predisposed to atherosclerotic changes consist of arteries exhibiting reduced shear forces [23]. In the absence of correct laminar flow, there is an increased phosphorylation of STAT3 and cytokine activation, e.g., TNFα with proinflammatory functions, as well as factors that intensify excessive and abnormal adherence of immune cells to the endothelium, including ICAM1, VCAM1, MCP1, and E-selectin. TNFα is also essential in enhancing the expression of VEGF-1, which is one of the main factors causing remodelling of the vascular wall and the formation of new vascular structures [6]. Wieczór and coleagues have demonstrated a similar correlation between VEGFA, sVEGFR1, sVEGFR2 and body weight in chronic ischaemia in the lower extremities caused by atherosclerosis (PAD). They reported that the average concentration of several angiogenic factors is considerably higher in people who are overweight or obese and who exhibit PAD, compared to healthy people [13].

The results of other studies indicated that neoangiogenesis might perform a significant function in the development of certain diseases including cancers that often coexist with obesity [24–27].

In colorectal cancers, a relationship between angiopoietin 1, angiopoietin 2, and tie-2 receptor and treatment response has been proven. Park reported that the effectiveness of chemotherapy was lower for patients whose tumour tissue had a high concentration of angiopoietin 2 [24].

An important role is attributed to VEGF in the development of some cancers [25–27]. The synthesis of VEGF is correlated with intracellular hypoxia and with the intracellular signalling mechanisms associated with the so-called NOTCH pathway. In ovarian cancer, there is a correlation between increased expression of NOTCH and production of VEGFR1 and 2 and, therefore, with metastasis [25]. This is a very important pathway in therapy with the antibody bevacizumab, which inhibits angiogenesis. It has also been shown that VEGF inhibitors may have a significant effect in the treatment of advanced breast cancer [26] or renal cancer [27].

There are also a number of studies that have investigated neoangiogenesis inhibitors in obesity treatment. Woo et al. [28] described the use of a natural extract derived from Melissa officinalis, which contains the active substance ALS-L1023, a compound that inhibits adipocyte hypertrophy in particular strains of obese mice. ALS-L1023 inhibits mRNA transcription of VEGFA and FGF 2, factors that stunt neoangiogenesis, a process that is necessary in proliferation of fat cells.

There are persuasive data showing that the inflammation of adipose tissue is caused by ischaemia associated with decreased capillary density and, consequently, decreased blood flow. Increased inflammatory cell migration was also observed. Hypoxia induces gene transcription of HIF factors (hypoxia induced factor) that affect the expression of VEGF, NFκB, IL6, apelin, visfatin, and CCL28 (CCL28 is a chemokine that functions as a ligand of CCR 8 and CCR 10 receptors on CD4 and CD8 lymphocytes). All of these HIF factors function as cytokines that escalate the inflammatory response [29]. A decrease in the density of capillaries in the adipose tissue of obese individuals was also observed [30] and, as demonstrated in another study, was correlated with a reduced level of VEGF mRNA, although there are differences in both the density and impact of angiogenesis between white and grey adipose tissue [31].

Conclusions

Angiogenesis and blood rheological changes are processes that accompany the complex physiological and pathophysiological processes of obesity. It is necessary to continue studies regarding the possibility that angiogenesis controls the adverse effects of obesity or its treatment.