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Adipose Tissue, Angiogenesis and Angio-MIR Under Physiological and Pathological Conditions

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Adipose Tissue, Angiogenesis and Angio-MIR Under Physiological and Pathological Conditions European Journal of Cell Biology 98 (2019) 53–64 Contents lists available at ScienceDirect European Journal of Cell Biology journal homepage: www.elsevier.com/locate/ejcb Review Adipose tissue, angiogenesis and angio-MIR under physiological and pathological conditions T ⁎ Anna Barbara Di Stefanoa,b, ,1, Daniela Massihniab,1, Federica Grisafia,b, Marta Castigliab, Francesca Toiaa, Luigi Montesanoa, Antonio Russob, Francesco Moschellaa, Adriana Cordovaa a Department of Surgical, Oncological and Oral Sciences, Section of Plastic and Reconstructive Surgery, University of Palermo, 90127 Palermo, Italy b Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy ARTICLE INFO ABSTRACT Keywords: Angiogenesis is a crucial process for the maintenance of normal tissue physiology and it is involved in tissue Adipose stem cells remodeling and regeneration. This process is essential for adipose tissue maintenance. The adipose tissue is Endothelial cells composed by different cell types including stromal vascular cells as well as adipose stem cells (ASCs). In par- Angiogenesis ticular, ASCs are multipotent somatic stem cells that are able to differentiate and secrete several growth factors; miRNAs they are recently emerging as a new cell reservoir for novel therapies and strategies in many diseases. Several studies suggest that ASCs have peculiar properties and participate in different disease-related processes such as angiogenesis. Furthermore, pathological expansion of adipose tissue brings to hypoxia, a major condition of unhealthy angiogenesis. Recent evidences have shown that microRNAs (miRNAs) play a crucial role also on ASCs as they take part in stemness maintenance, proliferation, and differentiation. It has been suggested that some miRNAs (MIR126, MIR31, MIR221 MIR222, MIR17-92 cluster, MIR30, MIR100 and MIR486) are directly involved in the angio- genic process by controlling multiple genes involved in this pathway. With the present review, we aim at pro- viding an updated summary of the importance of adipose tissue under physiological and pathological conditions and of its relationship with neovascularization process. In particular, we report an overview of the most im- portant miRNAs involved in angiogenesis focusing on ASCs. Hopefully the data presented will bring benefitin developing new therapeutic strategies. 1. Introduction skin epithelial, digestive tract, liver, and lungs cells (Orbay et al., 2012). They can be isolated, expanded and induced to differentiate Adipose tissue is a relevant metabolic and endocrine organ involved towards the above-mentioned lines under specific culture conditions. in various physiological functions, from heat production to hormone Recent studies have shown that, in many cell mechanisms, such as secretion. Adipose tissue is constantly evolving during lifetime and its stemness maintenance, proliferation and differentiation of ASCs, composition changes from childhood to adulthood. It contains several miRNAs play a pivot regulatory role through the modulation of several cell types such as stromal vascular cells, which includes also adipose receptors or ligands involved in these processes (Di Stefano et al., stem cells and endothelial progenitor cells. Adipose Stem Cells (ASCs) 2018). MicroRNAs are small non-coding RNA (18–20 base pairs) that are today a promising and attractive solution for regenerative medicine negatively regulate gene expression by inhibiting mRNA translation. due to their multipotent property (Leto Barone et al., 2013). ASCs are Numerous studies have focused on the identification of a specific characterized by a high plasticity and can differentiate both towards miRNA signature in ASCs during maintenance, remodeling and me- mesenchymal cells such as adipocytes, osteocytes, chondrocytes, en- senchymal differentiation including endothelial vessel formation. For dothelial cells, and towards ectodermal and endodermal cells such as this purpose, the term angio-miR was coined to identify specific classes ⁎ Corresponding author at: Department of Surgical, Oncological and Oral Sciences, Section of Plastic and Reconstructive Surgery, University of Palermo, via del Vespro 129, 90127 Palermo, Italy. E-mail addresses: [email protected] (A.B. Di Stefano), [email protected] (D. Massihnia), federica.grisafi@unipa.it (F. Grisafi), [email protected] (M. Castiglia), [email protected] (F. Toia), [email protected] (L. Montesano), [email protected] (A. Russo), [email protected] (F. Moschella), [email protected] (A. Cordova). 1 Equally contributed. https://doi.org/10.1016/j.ejcb.2018.11.005 Received 19 May 2018; Received in revised form 28 November 2018; Accepted 29 November 2018 0171-9335/ © 2018 Elsevier GmbH. All rights reserved. A.B. Di Stefano et al. European Journal of Cell Biology 98 (2019) 53–64 of miRNAs that are involved in the regulation of endothelial cells dif- protein 1 (UCP1) in mitochondrial contents, essential for catalysing ferentiation during angiogenesis (Suárez et al., 2008; Wang and Olson, nonshivering thermogenesis (Heaton et al., 1978). These cells seem to 2009). derive from a reversible transdifferentiation phenomenon also called Angiogenesis is a crucial process for the maintenance of normal “beiging effect” in which the WAT, under specific stimuli (cold ex- tissue physiology and it is involved in tissue remodeling and re- posure (Luo et al., 2017c), reduced light exposure, age or physical ex- generation (Viallard and Larrivée, 2017) through the formation of ercise (Lee, 2018)), can be transformed in BAT to supply the thermo- novel blood vessels network. The activation of angiogenesis is mediated genic needs or vice versa to increase storage capacity (Smorlesi et al., by specific biochemical signals (Carmeliet, 2000). Generally, this pro- 2012). Moreover, recently it has been described another adipocyte cell cess consists in multiple steps: stimulation and migration of endothelial type called “pink adipocytes” present during the gestation and lactation cells (ECs), degradation of the surrounding capillary basal lamina, period. They store lipids in the mammary gland and participate to se- formation of capillary sprout and finally vessels maturation (Rajabi and crete milk. After the lactation period, pink adipocytes disappear with Mousa, 2017). These events start in the embryonic stage and continue involution of the mammary glands (Cinti, 2018). throughout life (Balaj et al., 2013). The process is finely regulated by several pro- and anti-angiogenic factors. The main pro-angiogenic fac- 2.2. Adipose microenvironment tors involved in this process are the Vascular Endothelial Growth Factor (VEGF) family (VEGFA, VEGFB, VEGFC, VEGFD, VEGFE), and PGF1 Numerous signalling molecules compose the adipose micro- and 2 (placental growth factor) (Mashreghi et al., 2017). VEGF binds to environment that can positively and negatively modulate angiogenic Vascular Endothelial Growth Factor Receptor 1/2 (VEGFR1 and processes, homeostasis and vascular integrity regulating the interaction VEGFR2), encouraging angiogenesis through the stimulation of en- between vascular system and adipocytes. For example, while adipo- dothelial cells to produce proteolytic enzymes, which destroy the nectin negatively affects angiogenesis (Bråkenhielm et al., 2004b), perivascular extracellular matrix (ECM) and the basement membrane leptin induces angiogenesis, vascular fenestration and vascular re- (Rajabi and Mousa, 2017). Endothelial cells proliferate and migrate into modelling (Bouloumié et al., 1998; Cao et al., 2001). The vascular the perivascular area creating “primary sprouts”. The next phase leads network performs the same functions both in WAT and BAT and its to the formation of capillary loops, with the subsequent synthesis of a activity depends on the metabolic state of adipocytes. In a healthy new basement membrane and blood vessels maturation (Koch and person, vascular network of the adipose tissue has the role of trans- Distler, 2007). Even if angiogenesis is a physiological process, patho- porting hormones and the vessels are rich in fenestrations allowing the logical angiogenesis is one of the crucial steps for some diseases cor- passage of adipokines (Cao et al., 2001). Volume alteration of WAT related with adipose tissue such as obesity, diabetes, cardiovascular (both expansion or shrinkage), depending on energy consumption, is diseases, tumor growth and metastasis development (Carmeliet and needed for angiogenesis or vascular regression. For this reason, it has Jain, 2011). Hypertrophic conditions of adipose cells cause a hypoxic been demonstrated that there is a relationship between adipose and state in the tissue that leads to several pathological mechanisms in- vascular tissue (Harwood, 2012). Adipose vasculature is also closely volved with chronic inflammation or insulin resistance (Divella et al., related with “beiging effect” through the production of angiogenic 2016). factors such as VEGF, interleukin 4 (IL4) or angiopoietin that are re- This review describes the strict correlation between adipose tissue leased from WAT to induce new blood vessels formation. In particular, and angiogenic process, since there is a common ancestor. The angio- Park et al., demonstrated that VEGFA overexpression in adipocytes genic microenvironment is determinant for the disease development increases the number of beige adipocytes and induces vascularization of and adipose tissue is actively involved
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