ALIAmides: EXPERIMENTAL STUDIES ON THE CONTROL OF ANGIOGENESIS
Cipriano, Mariateresa (2011) ALIAmides: EXPERIMENTAL STUDIES ON THE CONTROL OF ANGIOGENESIS. [Tesi di dottorato] (Inedito)
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Generally, pathological conditions or altered physiological events are the consequences of different mechanisms altering the normal homeostasis. Between these events, angiogenesis that is the process that brings to the formation of new blood vessels from pre-existing ones, plays a very important role. The angiogenic process begins with capillary sprouting and culminates in formation of a new microcirculatory bed composed of arterioles, capillaries and venules. The initiation of angiogenesis consists of at least three processes: 1) breakdown of the basement membrane of the existing vessels, 2) migration of endothelial cells from the existing vessels towards an angiogenic stimulus, and 3) proliferation of endothelial cells (Klagsbrun & D’Amore, 1991). Physiological angiogenesis occurs during wound healing, organ regeneration, and in the female reproductive system during ovulation, menstruation, and the formation of the placenta; however, angiogenesis also occurs in pathological processes such as tumour growth, rheumatoid arthritis, diabetic retinopathy, and psoriasis. A switch to the angiogenic phenotype depends on a local change in the balance between angiogenic stimulators and inhibitors (Post et al., 2008), since this series of events is subject to a tight control played by the “angiogenic balance”, i.e. a physiological balance between the stimulatory and inhibitory signals for blood vessel growth, tightly controls angiogenesis (Folkman, 1995). Growing evidences suggest that angiogenesis occurs in the development of human pathologies affecting the Central Nervous System (CNS) too, although its role is controversial. In fact, new vascularisation should be protective in post- ischemic brain (Beck et al., 2009), in cerebral stroke (Arai et al., 2009), and in spinal cord injury (Han et al., 2010), where oxygen replacement is beneficial for neuronal cell survival in a hypoxic region. On the other hand, angiogenesis can be detrimental where inflammatory foci exist within the CNS, as in some neurodegenerative disorders (Candelario et al., 2009), since new blood supply may promote the increase of pro-oxidant, pro-inflammatory, and also pro- angiogenic mediators into the brain. Among these neurodegenerative conditions, a negative role of angiogenesis has been recently described during Alzheimer Disease (Fioravanzo et al., 2010). In fact, it seems to be clear that, during hyperactivation of astroglial cells, where a scenario of “reactive gliosis” is already in progress, the formation of new vessels gets the damaged area worse, in relation to the increase of pro-oxidant, pro-inflammatory and pro- angiogenic mediators and despite the assumption that angiogenesis brings oxygen and nutrients to the hypoxic place (Chrystov et al., 2006). In the periphery, a different cell type, mast cell, plays similarly to astroglia during neurodegeneration in sustaining angiogenic process. Actually, several evidences have shown the important role of mast cells in supporting angiogenesis (Iuvone et al., 1999), since their critical presence near sites of new capillary sprouting is a fundamental event for the new vessel formation. In fact, during specific pathological conditions, such as inflammatory or allergic diseases, mast cells become activated and allowed to degranulate, in releasing a series of pro- angiogenic mediators (VEGF, MMPs, TNF- α). In parallel, a new class of compounds, ALIAmides, (Autacoid Local Injury Antagonism Amides) possessing in vitro and in vivo anti- angiogenic activities, has been discovered (Aloe et al., 1993). Between these, recently it has been reported that Palmitoylethanolamide, ALIAmides’ ancestor, is able to inhibit both astroglial and mast cell activation (Scuderi et al., 2011; De Filippis et al., 2010). These evidences are the scientific starting point of my Ph.D. thesis, focused on studying the modulation of angiogenesis by ALIAmides through the control of astroglial and mast cell behaviour and leading, and, as a consequence, a modulation of both CNS and peripheral pathological inflammatory conditions.
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