脂肪组织血管生成

D 1 2 be 3Q1 4 A, UQ10 5 6 7 8 9 10 11 121314 15 16 Q12 17 18 19 20 Depot 21 22 23 24 25 26tiss 27ring 28adip 29ood 30ipo 31elo 32se 33ure 34mp 35nes 36oints to a deficit in adipose tissue angiogenesis as a contributing factor to insulin 37ease in obesity. These emerging findings support the concept of the adipose tissue 38 39 40 4142 43 44 45 46 es and 47 ization 48 on in in 49 aste pr 50 illance 51 lood flo 52 ue and 53 54 55 network.Most of the growthof organs and tissues occurs duringdevelop- 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76subcutaneous adipose tissue mass decreases the odds of insulin resis- 77 78 79 80 81eposition into muscle, 82tion and inappropriate 83 84 Biochimica et Biophysica Acta xxx (2013) xxx–xxx Q11 BBADIS-63743; No. of pages: 10; 4C: 3, 4, 6 Contents lists available at SciVerse ScienceDirect Biochimica et Bi j ourna l homepage: www.e ls are metabolic alterations that enhance risk of metabolic disease. The cellular and molecular mechanisms by which adipose tissue growth is lipid metabolism are thought to cause insulin resistance and result in a greatly increased risk of T2DM [4,5]. Thus, understanding the specific Uto expandhas clear evolutionary advantages, enabling survival in times ofnutrient scarcity; however, concomitant with adipose tissue expansion of triglycerides, thus preventing ectopic lipid dliver and visceral fat depots. Such ectopic deposi N Cment, and their final size remains relatively constant through adulthood. In contrast, adipose tissue is unique in that it can expand many-fold, to comprise more than 40% of total body composition in obese individuals, defined as a bodymass index of 30 or higher. The ability of adipose tissue tance by 48%. In contrast, each SD increase in visceral adipose tissue mass increases the odds of insulin resistance by 80% [3]. The protective effect of expandable subcutaneous fat depots duringweight gain is like- ly to bedue to their capacity to properly store excess calories in the form coordinated with the expansion of its capillar ☆ This article is part of a Special Issue entitled: Modulat and Disease. ⁎ Corresponding author at: Program in Molecular Medic Medical School, Worcester, MA 01605, USA. Tel.: +1 50885 E-mail address: Silvia.corvera@umassmed.edu (S. Co 0925-4439/$ – see front matter © 2013 Published by El http://dx.doi.org/10.1016/j.bbadis.2013.06.003 Please cite this article as: S. Corvera, O. Geale Acta (2013), http://dx.doi.org/10.1016/j.bba Thus, the growth of any lel growth of its vascular with increase risk, while expansion of others is associated with de- creased risk [2]. Strikingly, each standard deviation (SD) increase in Otion necessary for whole body homeostasis. organ or tissue must be accompanied by paral Capillary Blood vessel Hypoxia 1. Introduction The growth and function of all tissu pendent on their appropriate vascular for providing the correct oxygen tensi delivery and removal of nutrients andw of cells involved in tissue immune surve ical for the health of individual tissues, b growth factors that insure the inter-tiss R R E C TEModulation of Adipose Tissue in Health and Disease. © 2013 Published by Elsevier B.V. organs are critically de- . Blood flow is important dividual tissues, for the oducts, and for the transit . In addition to being crit- w delivers hormones and inter-organ communica- As these mechanisms may underlie the basis for adipose tissue dysfunc- tion in metabolic disease, they comprise a fertile and exciting area of research. While the close association between weight gain and heightened risk of type 2 diabetes (T2DM) is well established, not all individuals with obesity become diabetic, and certain individuals become diabetic after very minor weight gain [1]. This paradox is explained by the large individual variation in the size and expandability of different adi- pose tissue depots in humans, as expansion of some depots is associated Weight gain v asculature as a source of new targets for metabolic disease therapies. This article is part of a Special Issue entitled: Vascularization substantial amount of data p resistance and metabolic dis Review Adipose tissue angiogenesis: Impact on o Silvia Corvera ⁎, Olga Gealekman Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, M a b s t r a c ta r t i c l e i n f o Article history: Received 1 March 2013 Received in revised form 24 May 2013 Accepted 1 June 2013 Available online xxxx Keywords: Adipocyte Endothelial Vascular Fat The growth and function of of expanding many-fold du growing and proliferating angiogenesis, where new bl giogenesis may underlie ad In addition, genetic and dev pandability of diverse adipo the adipose tissue vasculat angiogenesis may directly i basic mechanisms of angioge y network are unknown. ion of Adipose Tissue in Health ine, University of Massachusetts 66898. rvera). sevier B.V. kman, Adipose tissue angioge dis.2013.06.003 P R O O F sity and type-2 diabetes☆ SA ues are critically dependent on their vascularization. Adipose tissue is capable adulthood, therefore requiring the formation of new vasculature to supply ocytes. The expansion of the vasculature in adipose tissue occurs through vessels develop from those pre-existing within the tissue. Inappropriate an- se tissue dysfunction in obesity, which in turn increases type-2 diabetes risk. pmental factors involved in vascular patterning may define the size and ex- tissue depots, which are also associated with type-2 diabetes risk. Moreover, appears to be the niche for pre-adipocyte precursors, and factors that affect act the generation of new adipocytes. Here we review recent advances on the is, and on the role of angiogenesis in adipose tissue development and obesity. A ophysica Acta evie r .com/ locate /bbad is 85mechanisms by which the subcutaneous adipose tissue expands is of 86particular interest, as these could provide new approaches for therapeu- 87tic intervention in metabolic disease. Several lines of evidence indicate 88that adipose tissue growth can be limited by its vascular supply [6–8], 89raising the possibility that the angiogenic potential of specific depots 90might be critical in limiting their maximal expandability. Testing this 91hypothesis will require a deep understanding of the basic mechanisms nesis: Impact on obesity and type-2 diabetes, Biochimica et Biophysica T 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187of tissue oxygen tension using microelectrodes [20–22]. Using directly 188placed microelectrodes, adipose tissue in obese humans has been found 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 2 S. Corvera, O. Gealekman / Biochimica et Biophysica Acta xxx (2013) xxx–xxx U N C O R R E C of vascularization in expanding adult tissues, and the specific regulatory factors that operate in different adipose tissue depots. 2. Basic molecular and cellular mechanisms of angiogenesis The de-novo formation of blood vessels during the development of the embryo occurs through the process of vasculogenesis, in which mesoderm-derived precursors, called angioblasts, organize into the first primitive blood vessels. All further vessel growth during organ and tissue development, as well as during tissue repair in adult organ- ism, takes place through the process of angiogenesis, in which new vessels sprout from pre-existing vasculature. It is likely therefore that the vascularization of adipose tissue depots in adults proceeds through angiogenic expansion of the existing vasculature, as has been shown to occur during the formation of fat pads from implanted cells [9]. The last few years have brought great insight into the basic molecular and cellular mechanisms of angiogenesis [10–14], setting the stage for the identification of factors that regulate this process to fulfill tissue and developmental stage specific functions. Key insights into the cellular andmolecular bases for angiogenesis, derived from experimentalmodels such as the developing zebrafish embryo and the mouse retina, are very briefly summarized below. The cardinal features of angiogenesis comprise the proliferation of endothelial cells, their directed migration through the extracellular matrix, the establishment of intercellular junctions, the formation of a lumen, the organization of perivascular supporting cells, the anasto- mosis with existing vessels, and the establishment of circulation. The cardinal initiating event is the stimulation of endothelial cell prolifer- ation, which is mediated by the VEGF family of growth factors. These growth factors and their receptors have been established as master regulators of endothelial cell growth. In particular, VEGF-A, acting through the VEGFR2 (VEGF receptor 2, also known as KDR in humans or Flk1 in mice) represents the most potent mitogenic and chemo attractant signal for endothelial cells. In response to VEGF-A gradients, endothelial cells divide, and acquire a specific phenotype (tip cell phe- notype) characterized by the formation of branches and numerous filopodia, which extend towards the direction in which the endothelial cell migrates. The action of VEGFs and their receptors are critically controlled by the Notch signaling pathway, which modulates the re- sponsiveness of endothelial cells to VEGF, and their subsequent special- ization. Thus, tip cells are characterized by high levels of expression of Delta-like 4 (Dll4), which is a ligand for Notch. The stimulation of Notch signaling by Dll4 in the tip cell suppresses VEGF signaling in ad- jacent cell, resulting in the acquisition of a stalk-cell phenotype. The continuous dynamic interaction between VEGF, Notch and Dll4 results in the development of angiogenic sprouts. Newly formed sprouts are then stabilized by interactions with smooth muscle cells and pericytes, and become lumenized, through processes that appear to involve junc- tional trans-membrane proteins such as VE-cadherin, as well as matrix proteins which are broken down and reorganized dynamically during vessel growth [14]. Newly formed sprouts anastomose with existing vessels, thus extending tissue microcirculation. While the basic steps of angiogenesis outlined above are expected to operate, it is likely that the vascular network of each organ and tissue will be established through key tissue-specificmechanisms. A prominent example is the regulation of angiogenesis in the central nervous system, where specific G-protein coupled receptors are uniquely expressed and play dominant roles in angiogenic vascularization of the developing brain [15,16].Whatmechanisms operate in adipose tissue, and how they modulate the basic steps of angiogenesis described above, are outstand- ing questions in adipose tissue biology. 3. Adipose tissue angiogenesis; what are the triggers? One of the guiding questions for understanding angiogenic growth in adipose tissue is whether themechanisms involved during embryonic Please cite this article as: S. Corvera, O. Gealekman, Adipose tissue angioge Acta (2013), http://dx.doi.org/10.1016/j.bbadis.2013.06.003 to be hypoxic [23]. Other findings consistent with a role for hypoxia are that the expression and secretion of pro-angiogenic factors by cultured adipocytes are strongly stimulated under low oxygen culture condi- tions [24]. These results suggest that, in a manner analogous to that oc- curring during tumor growth, adipose tissue hypoxia might be a driver for angiogenesis. However, the reported levels of hypoxia in human adipose tissue are relatively small, and one study actually finds increased oxygen tension in adipose tissue of obese subjects [25]. Moreover, it has been previously noted that expansion of adipose tissue in response to HFD is not accompanied by a corresponding increased blood flow [26]. Collectively, these results suggest that the response to hypoxia in adipose tissue may be insufficient to elicit sufficient compensatory angiogenic expansion. A powerful, direct approach to defining the role of hypoxia in adipose tissue growth has been the tissue-specific overexpression and ablation of both HIF-1α and HIF-1β. Overexpression of a constitutively active form of HIF-1α in adipose tissue failed to induce a pro-angiogenic response; rather, it resulted in a fibrotic response and an increase in local inflam- mation [27]. Conversely, ablation of HIF-1α or HIF-1β (ARNT) in adipose tissue reduced fat formation, and protected from HFD-induced obesity and insulin resistance [28,29]. Furthermore, anti-sense mediated deple- tion of HIF-1α in obese mice resulted in amelioration of HFD-induced insulin resistance [30], as did pharmaceutical inhibition of HIF-1α, as well as inducible expression of a dominant negative form [31]. Overall, these results are consistent with a model where adipose tissue hypoxia induces HIF-1α, which induces a fibrotic and inflammatory response rather than a compensatory pro-angiogenic response. Nevertheless, E D P R O O F and early postnatal development are similar to those involved in re- sponse to excess calorie consumption in adults. In both cases, two broad possibilities can be considered: First, angiogenic expansion may be triggered in response to signals emanating from proliferating and en- larging adipocytes. The second possibility is that angiogenic growth is triggered by developmental and/or metabolic signals, and parallels or precedes adipocyte proliferation and enlargement (Fig. 1). These two possibilities are not mutually exclusive, and in all likelihood tissue ex- pansion involves both local cues arising from expanding adipocytes, as well as distant cues reflecting the developmental and metabolic states of the whole organism. The first option, in which vascular growth ensues secondarily to parenchymal growth is the canonical model for oncogenic vasculari- zation [17–19]. In this model, the rapid growth of tumor cells and the formation of a tumor mass elicit regions of hypoxia. Hypoxia is sensed through multiple mechanisms, prominent amongst which is the inactivation of oxygen-dependent prolyl-hydroxylases. Inactivation of these enzymes results in the protection of HIF-1α from proteolytic degradation, allowing its dimerization with constitutively expressed HIF-1β to form the functional transcription factorHIF1. This transcription factor potently activates a program of hypoxia adaptation, which in- cludes decreased transcription and translation and increased VEGF-A expression. The angiogenic expansion of the vasculature in response to VEGF-A enhances blood flow and relieves hypoxia, allowing further tumor growth. This model, in which tumor growth is absolutely depen- dent on stimulation of angiogenesis, forms the basis for the development and use of anti-angiogenic therapies in cancer [11]. 4. Role of hypoxia in adipose tissue angiogenesis Themost relevant evidence consistentwith a possible role for hypoxia in adipose tissue angiogenesis are the findings that adipose tissue in ro- dents becomes hypoxic in response to obesity that is rapidly induced by high fat diet (HFD). This finding has been documented repeatedly, using both chemical indicators of hypoxia, as well as direct monitoring 216HIF-1α may be relevant for the growth and maintenance of brown nesis: Impact on obesity and type-2 diabetes, Biochimica et Biophysica T217 adipose tissue, as expression of dominant-negative form of HIF-1α218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 rowt sue cha te h 3S. Corvera, O. Gealekman / Biochimica et Biophysica Acta xxx (2013) xxx–xxx impairs thermogenesis and energy expenditure [32]. Fig. 1. Two possible models for the stimulation of angiogenesis during adipose tissue g generating areas of tissue hypoxia. Hypoxia, and/or other factors released from the tis tissue architecture and function. B. Increased calorie consumption results in systemic adipose tissue. Increased angiogenesis facilitates lipid storage in adipocytes and adipocy opment of hypoxia and metabolic stress. U N C O R R E C5. Role of VEGF in adipose tissue angiogenesis In tumor angiogenesis, hypoxia-induced HIF1 stabilization activates VEGF transcription and secretion, which in turn stimulates angiogene- sis. The induction of fibrosis and inflammation by HIF-1α in adipose tis- sue suggests that the stimulation of VEGF productionmay be controlled by different mechanisms, which are insufficiently activated during the rapid expansion induced by high-fat diets or hyperphagia. Consistent with this notion, transgenic overexpression of VEGF in adipose tissue results in increased vascularization, decreased inflammation, and ame- lioration of HFD-induced insulin resistance [33–35]. More strikingly, induced expression of VEGF-A in adipose tissue of animals previously rendered obese and insulin resistant reversed the establishedmetabolic defects [33]. Expression of VEGF-A also caused the generation of adipo- cytes expressing UCP1, which are more similar to brown adipose tissue and have a highermetabolic rate, and result in lowerweight gain under conditions of HFD [36]. Conversely, ablation of VEGF in adipose tissue resulted in hypo- perfused adipose tissue, which displayed higher levels of inflammato- ry markers even under normal chow diet. In response to HFD feeding adipose tissue from VEGF-ablated animals developed much greater inflammation compared to controls [33]. This greater inflammation was accompanied by adipocyte death, a net decrease in depot size, and marked deterioration of glucose tolerance and insulin sensitivity. This enhanced inflammatory phenotype is similar to that observed in animals overexpressing HIF-1α. In aggregate, these findings suggest a model where insufficient angiogenesis during high-fat diet leads to hypoxia, HIF-1α expression, inflammation and adipose tissue dysfunc- tion (Fig. 2). In addition, these studies clearly demonstrate that increased VEGF-A production and increased vascularization enable adipose tissue to adapt to rapid expansion caused by acutely increased caloric intake, Please cite this article as: S. Corvera, O. Gealekman, Adipose tissue angioge Acta (2013), http://dx.doi.org/10.1016/j.bbadis.2013.06.003 E D P R O O F and protect from the development of insulin resistance and glucose intolerance. These results raise the questions: whatmechanisms limit the expres- h. A. Increased calorie consumption results in adipocyte hypertrophy and hyperplasia, stimulate angiogenesis. Angiogenesis results in mitigation of hypoxia and appropriate nges in trophic factors such as insulin, which directly stimulate angiogenesis within yperplasia. The simultaneous expansion of adipocytes and vasculature prevents devel- 252sion of VEGF in adipose tissue, and do differences in VEGF production ac- 253count for the variation in human adipose tissue expandability and 254subsequent protection from inflammation and metabolic dysfunction? 255Although some studies report decreased levels of VEGF gene expression 256in obese humans [23], others report higher levels of expression of 257VEGF-A in both subcutaneous and omental fat in obese compared 258to lean subjects, and a higher level in omental adipose tissue from 259obese insulin-sensitive compared to obese insulin-resistant individuals 260[37]. Unpublished results from our own group studying obese female 261subje