Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases But owing to several unanswered questions, caution is needed

Angiogenesis in cancer and other diseases

The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution However, the presence of excess adipose tissue can be maladaptive A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system Leptin also signals nutritional status to several other physiological systems and modulates their function Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity

Leptin and the regulation of body weight in mammals

White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name 'adipocytokines' or 'adipokines'. However, since most are neither 'cytokines' nor 'cytokine-like', it is recommended that the term 'adipokine' be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fatty acids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFalpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.

/pdf/adipokines-inflammation-and-the-pleiotropic-role-of-white-3w4f0cu9tn.pdf

Adipokines: inflammation and the pleiotropic role of white adipose tissue.

Obesity is associated with a state of chronic, low-grade inflammation. Two manuscripts in this issue of the JCI (see the related articles beginning on pages 1796 and 1821) now report that obese adipose tissue is characterized by macrophage infiltration and that these macrophages are an important source of inflammation in this tissue. These studies prompt consideration of new models to include a major role for macrophages in the molecular changes that occur in adipose tissue in obesity.

/pdf/obesity-induced-inflammatory-changes-in-adipose-tissue-1d9ldp35me.pdf

Obesity-induced inflammatory changes in adipose tissue

Background— Adipose tissue development and remodeling are closely associated with the growth of vascular network. We hypothesized that adipose tissue may contain progenitor cells with angiogenic potential and that therapy based on adipose tissue-derived progenitor cells administration may constitute a promising cell therapy in patients with ischemic disease. Methods and Results— In mice, cultured stromal-vascular fraction (SVF) cells from adipose tissue have a great proangiogenic potential, comparable to that of bone marrow mononuclear cells in the mouse ischemic hindlimb model. Similarly, cultured human SVF cells differentiate into endothelial cells, incorporate into vessels, and promote both postischemic neovascularization in nude mice and vessel-like structure formation in Matrigel plug. In vitro, these cells represent a homogeneous population of CD34- and CD13-positive cells, which can spontaneously express the endothelial cell markers CD31 and von Willebrand factor when cultured in semisolid medium. ...

/pdf/plasticity-of-human-adipose-lineage-cells-toward-endothelial-nz457uji15.pdf

Plasticity of Human Adipose Lineage Cells Toward Endothelial Cells Physiological and Therapeutic Perspectives

Leptin is a hormone that regulates food intake, and its receptor (OB-Rb) is expressed primarily in the hypothalamus. Here, it is shown that OB-Rb is also expressed in human vasculature and in primary cultures of human endothelial cells. In vitro and in vivo assays revealed that leptin has angiogenic activity. In vivo, leptin induced neovascularization in corneas from normal rats but not in corneas from fa/fa Zucker rats, which lack functional leptin receptors. These observations indicate that the vascular endothelium is a target for leptin and suggest a physiological mechanism whereby leptin-induced angiogenesis may facilitate increased energy expenditure.

https://science.sciencemag.org/content/sci/281/5383/1683.full.pdf

Biological Action of Leptin as an Angiogenic Factor

Transcriptional Activation of the Human Leptin Gene in Response to Hypoxia INVOLVEMENT OF HYPOXIA-INDUCIBLE FACTOR 1

Leptin, a 16 kDa pleiotropic cytokine primarily expressed in adipose tissue, has been shown to cause multiple systemic biological actions. Recently, leptin has also been documented as an important component of the wound healing process and its receptor appears to be expressed in wound tissue. We have previously demonstrated that leptin is a potent angiogenic factor exerting direct effects on endothelial cells and that transcription of its encoding gene is regulated by hypoxia. Here, we hypothesize that leptin expression is acutely up-regulated in the ischemic tissue of experimental wounds. Using a combination of in situ hybridization and quantitative RT-PCR experiments, we show that leptin expression is rapidly and steadily up-regulated in skin tissue from incisional and excisional wounds. By immunohistochemistry, we demonstrate increased and sustained leptin protein levels in basal keratinocytes, blood vessel walls, and fibroblasts. To determine whether leptin is required for normal healing, excisional wounds were treated with neutralizing anti-leptin antibodies. This treatment markedly hampered healing progression and prevented wound closure and contraction. Finally, a transient rise in circulating blood leptin levels was detected within the first 24 h after inflicting the injury; we present evidence suggesting that this elevation is due to increased leptin production at the ischemic wound site. We conclude that leptin is acutely up-regulated in the injured skin and propose that this local production of leptin serves a critical functional role as an autocrine/paracrine regulator of normal wound healing.

https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.03-0068fje

Leptin is an autocrine/paracrine regulator of wound healing

This invention relates to regulatable recombinant expression constructs that provide regulated gene expression of mammalian genes.

Jaime Flores-Riveros

Papers

Biological Action of Leptin as an Angiogenic Factor

Transcriptional Activation of the Human Leptin Gene in Response to Hypoxia INVOLVEMENT OF HYPOXIA-INDUCIBLE FACTOR 1

Leptin is an autocrine/paracrine regulator of wound healing

Regulated expression of recombinant DNA