Vascularization of the trachea in the bottlenose dolphin: Comparison with bovine and evidence for evolutionary adaptations to diving

The rigid structure of the mammalian trachea is functional to maintain constant patency and airflow during breathing, but no gas exchange takes place through its walls. The structure of the organ in dolphins shows increased rigidity of the tracheal cartilaginous rings and the presence of vascular lacunae in the submucosa. However, no actual comparison was ever made between the size and capacity of the vascular lacunae of the dolphin trachea and the potentially homologous structures of terrestrial mammals. In the present study, the extension of the lacunae has been compared between the bottlenose dolphin and the bovine, a closely related terrestrial Cetartiodactyla. Our results indicate that the extension of the blood spaces in the submucosa of dolphins is over 12 times larger than in the corresponding structure of the bovines. Furthermore, a microscopic analysis revealed the presence of valve-like structures in the walls of the cetacean lacunae. The huge difference in size suggests that the lacunae are not merely a product of individual physiological plasticity, but may constitute a true adaptive evolutionary character, functional to life in the aquatic environment. The presence of valve-like structures may be related to the regulation of blood flow, and curtail excessive compression under baric stress at depth

An update on somatostatin receptor signaling in native systems and new insights on their pathophysiology

The peptide somatostatin (SRIF) has important physiological effects (mostly inhibitory) which have formed the basis for the clinical use of SRIF compounds. SRIF binding to its five G-protein coupled receptors leads to the modulation of multiple transduction pathways. However, our current understanding of signalling exerted by receptors endogenously expressed in different cells/tissues reflects a rather complicated picture. On the other hand, the complexity of SRIF receptor signalling in pathologies, including pituitary and nervous system diseases, may be studied not only as alternative intervention points for the modulation of SRIF function but also to exploit new chemical space for drug-like molecules.L'articolo è disponibile sul sito dell'editore http://www.sciencedirect.com

Multiple Signalling Transduction Mechanisms Differentially Coupled to Somatostatin Receptor Subtypes: a Current View.

Somatostatin (SRIF) is a cyclic peptide widely distributed throughout the body with important physiological effects (mostly inhibitory) on several organ systems. SRIF may act as a neurohormone, neurotransmitter, neuromodulator or as a local factor, and exhibits potent antiproliferative activity. SRIF effects have formed the basis for the clinical use of SRIF analogues in the treatment of endocrine tumours, acromegaly and gastrointestinal disorders. Several data suggest that SRIF may also be a therapeutic target in a number of different diseases. The binding of SRIF to its five G-protein coupled receptors leads to modulation of multiple transduction pathways, including adenylyl cyclase, guanylyl cyclase, phospholipase C, K+ and Ca2+ channels, phospholipase A2, nitric oxide, Na+/H+ exchanger, protein phosphatases and MAP kinases. The diversity of the transduction pathways reflects the pleiotropic actions of SRIF. However, our current understanding depicts a rather complicated picture and conflicting results have also been reported. Data are mostly based on in vitro experiments, and parallels with the real in vivo conditions are not so obvious. Due to the clinical relevance of the SRIF system, the elucidation of the intracellular role of endogenous SRIF receptors may offer new therapeutic perspectives. These will enable development of specific pharmacological signalling modulators which can be incorporated into the therapeutic arsenal. The present review represents a detailed and exhaustive summary which covers the latest advances in the transduction pathways of SRIF receptors.L'articolo è disponibile sul sito dell'editore http://www.benthamscience.com/index.ht

Physiology and pathology of somatostatin in the mammalian retina: a current view

In the retina, peptidergic signalling participates in multiple circuits of visual information processing. The neuropeptide somatostatin (SRIF) is localised to amacrine cells and, in some instances, in a subset of ganglion cells. The variegated expression patterns of SRIF receptors (sst1-sst5) and the variety of signalling mechanisms activated by retinal SRIF suggest that this peptide may exert multiple actions on retinal neurons and on retinal physiology, although our current understanding reflects a rather complicated picture. SRIF, mostly through sst2, may act as a positive factor in the retina by regulating retinal homeostasis and protecting neurons against damage. In this respect, SRIF analogues seem to constitute a promising therapeutic arsenal to cure different retinal diseases, as for instance ischemic and diabetic retinopathies. However, further investigations are needed not only to fully understand the functional role of the SRIF system in the retina but also to exploit new chemical space for drug-like molecules.L'articolo è disponibile sul sito dell'editore http://www.sciencedirect.com

Molecular and Cellular Mechanisms Underlying Somatostatin-Based Signaling in Two Model Neural Networks, the Retina and the Hippocampus

Neural inhibition plays a key role in determining the specific computational tasks of different brain circuitries. This functional \u201cbraking\u201d activity is provided by inhibitory interneurons that use different neurochemicals for signaling. One of these substances, somatostatin, is found in several neural networks, raising questions about the significance of its widespread occurrence and usage. Here, we address this issue by analyzing the somatostatinergic system in two regions of the central nervous system, the retina and the hippocampus. By comparing the available information on these structures, we have identified common motifs in the action of somatostatin that may explain its involvement in such diverse circuitries. The emerging concept is that somatostatin-based signaling, through conserved molecular and cellular mechanisms, allows neural networks to operate correctly

Changing distribution of GABA-like immunoreactivity in pigeon visual areas during the early posthatching period and effects of retinal removal on tectal GABAergic systems

The distribution of GABA-like immunoreactivity in the pigeon visual system was studied during the first 9 days after hatching using a mouse monoclonal antibody, mAb 3A12, to glutaraldehyde linked GABA (Matute & Streit, 1986). GABA-like immunoreactivity was seen in cell bodies as well as in neuropil at the level of both the retina and central visual regions at any posthatching age. However, the distribution of putative GABAergic cells and processes varied with age reaching the adult pattern at around 9 days. As a general observation, almost no cell bodies in the retina (except for some perikarya in the ganglion cell layer) were labeled at hatching but densely packed immunostained processes were present in the inner plexiform layer. During the next few days, GABA-immunoreactive amacrine and horizontal cells appeared and the adult distribution of GABA-like immunoreactivity was reached at around 9 days. In the other visual regions examined, the general trend in the variation of GABA-like immunoreactivity included: (1) a progressive decrease in the density of immunostained cell bodies and (2) an almost parallel increase in the concentration of stained neuropil. Since in pigeons the adult organization of visual pathways and the final distribution putative GABAergic systems are reached at around the same age, we suggest the possibility that incoming ganglion cell axons play a role in regulating the distribution of GABA-like immunoreactivity in Visual areas. This hypothesis is supported by the fact that the distribution of GABA-like immunoreactivity in the superficial layers of the optic tectum was altered following ablation of the contralateral retina immediately after hatchin

Antiangiogenic role of somatostatin receptor 2 in a model of hypoxia-induced neovascularization in the retina: Results from transgenic mice

PURPOSE. To determine whether the somatostatin receptor 2 (sst2) influences angiogenesis and its associated factors in a model of hypoxia-induced retinal neovascularization. METHODS. sst1-knockout (KO) mice, in which sst2 is overexpressed and overfunctional, and sst2-KO mice were used. Angiogenesis was evaluated in fluorescein-perfused retinas. Angiogenesis- associated factors were determined by RT-PCR and immunohistochemistry. RESULTS. Retinal neovascularization was increased in sst2-KO mice, but remained unchanged in sst1-KO compared with wild-type (WT) mice. Retinal levels of sst2 mRNA were not affected by hypoxia. Normoxic levels of angiogenesis regulators were similar in WT and KO retinas except for mRNA levels of IGF-1, Ang-2, and its receptor Tie-2. In WT, hypoxia induced an increase in mRNA levels of (1) VEGF and its receptors, (2) IGF-1R, and (3) Ang-2 and Tie-2. The increase in VEGF and IGF-1R mRNAs was more pronounced after sst2 loss, but was less pronounced when sst2 was overexpressed. In addition, in hypoxic retinas, sst2 loss increased IGF-1 mRNA, whereas it decreased Ang-1, Tie-1, and Tie-2 mRNA levels. Moreover, Tie-1 mRNA increased when sst2 was overexpressed. Immunohistochemistry confirmed the results in hypoxic retinas on increased expression of VEGF, IGF-1, and their receptors after sst2 loss. It also allowed the localization of these factors to specific retinal cells. In this respect, VEGFR-2, IGF-1, and IGF-1R were localized to Mu¨ller cells. CONCLUSIONS. These results suggest that sst2 may be protective against angiogenesis. The immediate clinical importance lies in the establishment of a potential pharmacological target based on sst2 pharmacology.L'articolo è disponibile sul sito dell'editore http://www.arvo.org/eweb/StartPage.aspx?Site=arvo

Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa

Background: In retinitis pigmentosa (RP), inherited rod death is followed by cone loss and blindness. Why cones die is still a matter of consideration. Here, we investigate the pathogenic role of the sympathetic transmission in the rd10 mouse model of RP. Methods: Retinal levels of beta adrenergic receptor (BAR) 2 and norepinephrine (NE) were measured. After administration of the BAR1/2 blocker propranolol or the hypoxia-inducible factor (HIF)-1 activator dimethyloxalylglycine (DMOG), retinal levels of HIF-1α, BAR2 or proteins involved in BAR2 desensitization were also measured. In DMOG treated mice, expression and localization of BAR2, inflammatory markers and cone arrestin were determined. Finally, rd10 mice were subjected to electroretinogram (ERG) analysis to assess rod and cone function. Results: In the rd10 retina, BAR2 overexpression and NE accumulation were found, with BAR2 immunoreactivity localized to Müller cells. BAR2 overexpression was likely due to desensitization defects. Upregulated levels of BAR2 were drastically reduced by propranolol that also restored desensitization defects. Due to the low level of HIF-1 consequent to the hyperoxic environment in the rd10 retina, we hypothesized a link between HIF-1 and BAR2. HIF-1α stabilization with DMOG resulted in i. increased HIF-1α accumulation, ii. decreased BAR2 levels, iii. restored desensitization processes, iv. reduced expression of inflammatory markers and v. increased cone survival without improved retinal function. Conclusions: Our results support a pathogenic role of the sympathetic system in RP that might help to understand why rd10 mice show a positive response to BAR blockers

The β3 adrenoceptor in proliferative retinopathies: "Cinderella" steps out of its family shadow

: In the retina, hypoxic condition leads to overgrowing leaky vessels resulting in altered metabolic supply that may cause impaired visual function. Hypoxia-inducible factor-1 (HIF-1) is a central regulator of the retinal response to hypoxia by activating the transcription of numerous target genes, including vascular endothelium growth factor, which acts as a major player in retinal angiogenesis. In the present review, oxygen urge by the retina and its oxygen sensing systems including HIF-1 are discussed in respect to the role of the beta-adrenergic receptors (β-ARs) and their pharmacologic manipulation in the vascular response to hypoxia. In the β-AR family, β1- and β2-AR have long been attracting attention because their pharmacology is intensely used for human health, while β3-AR, the third and last cloned receptor is no longer increasingly emerging as an attractive target for drug discovery. Here, β3-AR, a main character in several organs including the heart, the adipose tissue and the urinary bladder, but so far a supporting actor in the retina, has been thoroughly examined in respect to its function in retinal response to hypoxia. In particular, its oxygen dependence has been taken as a key indicator of β3-AR involvement in HIF-1-mediated responses to oxygen. Hence, the possibility of β3-AR transcription by HIF-1 has been discussed from early circumstantial evidence to the recent demonstration that β3-AR acts as a novel HIF-1 target gene by playing like a putative intermediary between oxygen levels and retinal vessel proliferation. Thus, targeting β3-AR may implement the therapeutic armamentarium against neovascular pathologies of the eye