Role of VPAC1 and VPAC2 in VIP mediated inhibition of rat pulmonary artery and aortic smooth muscle cell proliferation

Hilaire, Rose‐Claire St.; Murthy, Subramanyam N.; Kadowitz, Philip J.; Jeter, James R.

doi:10.1016/j.peptides.2010.04.024

Cited by 19 publications

(15 citation statements)

References 15 publications

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“…The most significant genes in both regions were occludin ( OCLN , HR = 8.6, CI = 2.6–29.0, p = 4.9E‐04) and vasoactive intestinal peptide receptor 2 ( VIPR2 , HR = 4.5, CI = 1.4–14.3, p = 1.2E‐02). OCLN encodes a tight‐junction protein, whereas VIPR2 is a negative regulator of smooth muscle cell proliferation . No amplified regions correlated with survival.…”

Section: Resultsmentioning

confidence: 99%

Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways

Cuppens

Moisse

Depreeuw

et al. 2017

Intl Journal of Cancer

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Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.

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Section: Resultsmentioning

confidence: 99%

Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways

Cuppens

Moisse

Depreeuw

et al. 2017

Intl Journal of Cancer

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“…Similar findings have been reported in porcine basilar arteries, where VPAC1 was expressed in the endothelium and VPAC2 in the outer layer of the smooth muscle (Grant et al 2006). Expression of both VIP receptors was also demonstrated by immunohistochemistry in tissue sections of the aorta and pulmonary artery as well as in cultured smooth muscle cells from these vessels (St Hilaire et al 2010). In contrast, only VPAC1 expression was reported in rat cerebral arteries and arterioles, and these receptors were observed in the plasmalemma of circular smooth muscles, but not in the endothelium (Fahrenkrug et al 2000).…”

Section: Discussionmentioning

confidence: 98%

Mechanisms of VIP‐induced inhibition of the lymphatic vessel pump

Weid

Rehal

Dyrda

et al. 2012

The Journal of Physiology

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Key points• Lymphatic pumping is characterized by the ability of collecting lymphatic vessels to contract in a phasic manner to propel lymph. This activity is critical for tissue fluid homeostasis and immune cell transport to lymph nodes.• Vasoactive intestinal peptide (VIP) is a neuro-immuno-modulator with anti-inflammatory properties released by peptidergic nerves and by inflammatory cells patrolling the interstitium and lymph.• Here we report that VIP is present in lymphatic vessels as well as in the lymph and that it potently inhibits lymphatic pumping and hyperpolarizes the lymphatic muscle via stimulation of VPAC2 VIP receptors, activation of protein kinase A and opening of ATP-sensitive K + channels.• These results suggest an important role for VIP in inhibiting lymphatic pumping. This process might become critical during inflammation, where it would lead to decreased lymph drainage, oedema formation and compromised immune cell trafficking.Abstract Lymphatic vessels serve as a route by which interstitial fluid, protein and other macromolecules are returned to the blood circulation and immune cells and antigens gain access to lymph nodes. Lymph flow is an active process promoted by rhythmical contraction-relaxation events occurring in the collecting lymphatic vessels. This lymphatic pumping is an intrinsic property of the lymphatic muscles in the vessel wall and consequent to action potentials. Compromised lymphatic pumping may affect lymph and immune cell transport, an action which could be particularly detrimental during inflammation. Importantly, many inflammatory mediators alter lymphatic pumping. Vasoactive intestinal peptide (VIP) is a neuro-and immuno-modulator thought to be released by nerve terminals and immune cells in close proximity to lymphatic vessels. We demonstrated the presence of the peptide in lymphatic vessels and in the lymph and examined the effects of VIP on mesenteric collecting lymphatic vessels of the guinea pig using pharmacological bioassays, intracellular microelectrode electrophysiology, immunofluorescence and quantitative real-time PCR. We showed that VIP alters lymphatic pumping by decreasing the frequency of lymphatic contractions and hyperpolarizing the lymphatic muscle membrane potential in a concentration-dependent manner. Our data further suggest that these channels. Inhibition of lymphatic pumping by VIP may compromise lymph drainage, oedema resolution and immune cell trafficking to the draining lymph nodes.

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“…VIP was shown to induce VEGF-a expression and enhance angiogenesis in murine ischemia as well as in human prostate and breast cancer cell lines (59)(60)(61). VIP has antiproliferative effects on smooth muscle vascular cells, and smooth muscle-cell apoptosis is involved in vascular transformation during early pregnancy (62). There are no reports on angiopoietin 1 or sENG and VIP in pregnancy in other cell types.…”

Section: Discussionmentioning

confidence: 99%

Trophoblast VIP deficiency entails immune homeostasis loss and adverse pregnancy outcome in mice

et al. 2018

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Immune homeostasis maintenance throughout pregnancy is critical for normal fetal development. Trophoblast cells differentiate into an invasive phenotype and contribute to the transformation of maternal arteries and the functional shaping of decidual leukocyte populations. Insufficient trophoblast invasion, inadequate vascular remodeling, and a loss of immunologic homeostasis are associated with pregnancy complications, such as preeclampsia and intrauterine growth restriction. Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide synthetized in trophoblasts at the maternal-placental interface. It regulates the function of trophoblast cells and their interaction with decidual leukocytes. By means of a murine model of pregnancy in normal maternal background with VIP-deficient trophoblast cells, here we demonstrate that trophoblast VIP is critical for trophoblast function: VIP gene haploinsufficiency results in lower matrix metalloproteinase 9 expression, and reduced migration and invasion capacities. A reduced number of regulatory T cells at the implantation sites along with a lower expression of proangiogenic and antiinflammatory markers were also observed. Findings detected in the implantation sites at early stages were followed by an abnormal placental structure and lower fetal weight. This effect was overcome by VIP treatment of the early pregnant mice. Our results support the relevance of trophoblast-synthesized VIP as a critical factor in vivo for trophoblast-cell function and immune homeostasis maintenance in mouse pregnancy.-Hauk, V., Vota, D., Gallino, L., Calo, G., Paparini, D., Merech, F., Ochoa, F., Zotta, E., Ramhorst, R., Waschek, J., Leirós, C. P. Trophoblast VIP deficiency entails immune homeostasis loss and adverse pregnancy outcome in mice.

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Role of VPAC1 and VPAC2 in VIP mediated inhibition of rat pulmonary artery and aortic smooth muscle cell proliferation

Cited by 19 publications

References 15 publications

Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways

Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways

Mechanisms of VIP‐induced inhibition of the lymphatic vessel pump

Trophoblast VIP deficiency entails immune homeostasis loss and adverse pregnancy outcome in mice

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