Vasoactive intestinal peptide induces both tyrosine hydroxylase activity and tetrahydrobiopterin biosynthesis in PC12 cells

Anastasiadis, P; Bezin, Laurent; Gordon, L. J.; Imerman, Bruce A.; Blitz, Jennifer; Levine, Robert A.

doi:10.1016/s0306-4522(97)00611-8

Cited by 22 publications

(22 citation statements)

References 74 publications

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“…VIP exerts many of the actions highlighted by deletion of its gene, including: 1) increased generation of cyclic adenosine monophosphate (cAMP) and resultant protein kinase (PK)A activation; 2) enhancement of NOS3 activity and NO production via activation of BH4 [21], and hence of guanylate cyclase activity; 3) neutralisation of the contractile effect of endothelin on pulmonary arterial segments and abrogation of the heightened expression of lung endothelin receptors A and B during hypoxia [22]; 4) suppression of PASMC proliferation by In addition to its vascular effects, VIP has a number of important anti-inflammatory effects, including: 1) modulation of T-cell proliferation and activation; 2) inhibition of nuclear factor-kB activation; 3) suppression of pro-inflammatory cytokines TNF-a, IL-6, IL-12, IL-18, chemokine regulated on activation, normal T-cell expressed and secreted (RANTES), and inducible NOS; and 4) upregulation of anti-inflammatory IL-10 [24].…”

Section: Discussionmentioning

confidence: 99%

Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion: Table 1—

Hamidi

Prabhakar²,

Said³

2007

Eur Respir J

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The pathogenesis of idiopathic pulmonary arterial hypertension (PAH) remains poorly understood. The present authors recently reported that mice with vasoactive intestinal peptide (VIP) gene disruption show a spontaneous phenotype of PAH, with pulmonary vascular remodelling and lung inflammation.To explore the underlying molecular mechanisms in this model, it was examined whether absence of the VIP gene might alter the expression of additional genes involved in the pathogenesis of PAH, as single-gene deletions, in the absence of hypoxia, rarely result in significant pulmonary vascular remodelling.Lung tissue from mice with targeted disruption of the vasoactive intestinal peptide gene (VIP -/-mice) and from control mice was subjected to whole-genome gene microarray analysis, and the results validated with quantitative, real-time PCR. Lungs from VIP -/-mice showed a wide range of significant gene expression alterations, including overexpression of genes that promote pulmonary vascular smooth muscle cell proliferation, underexpression of antiproliferative genes and upregulation of pro-inflammatory genes.In conclusion, vasoactive intestinal peptide is a pivotal modulator of genes controlling the pulmonary vasculature, its deficiency alone resulting in gene expression alterations that can readily explain both the vascular remodelling and associated inflammatory response in pulmonary arterial hypertension. The present findings shed more light on the molecular mechanisms of pulmonary arterial hypertension, and could lead to better understanding of the pathogenesis of human pulmonary arterial hypertension, and hence to improved therapy. KEYWORDS: Gene expression and regulation, pulmonary hypertension, quantitative PCR, right heart failure T he present authors recently described a model of pulmonary hypertension in airbreathing, nonhypoxaemic mice with targeted disruption of the vasoactive intestinal peptide (VIP) gene (VIP -/-mice) [1]. The pulmonary vascular abnormalities in these mice, notably pulmonary vascular smooth muscle and collagen proliferation, and right ventricular (RV) hypertrophy are reminiscent of those seen in idiopathic pulmonary arterial hypertension (IPAH). There was also evidence of lung inflammation, which may contribute to the pathogenesis of IPAH. Both the vascular remodelling and inflammation were markedly attenuated by VIP replacement [1]. This mouse model, however, differs from the human disease in several respects: 1) pulmonary hypertension is of a moderate degree; 2) despite often pronounced medial thickening, intimal proliferation and plexiform lesions are not observed; and 3) in contrast to the clinical condition, the mouse phenotype is more prominently expressed in males than in females.The purpose of the present study was to uncover the molecular mechanisms by which disruption of the VIP gene could lead to expression of pulmonary arterial hypertension (PAH), pulmonary vascular remodelling, RV hypertrophy and lung inflammation. VIP has long been identified as a pulmonary, as well ...

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Section: Discussionmentioning

confidence: 99%

Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion: Table 1—

Hamidi

Prabhakar²,

Said³

2007

Eur Respir J

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“…On the other hand, the gene for adrenomedullin, a pulmonary vasodilator and antiproliferative peptide, was significantly downregulated. VIP also has been demonstrated to induce the biosynthesis of tetrahydrobiopterin, 45 a critical cofactor in endothelial nitric oxide synthase function. 46 Thus, the lack of the VIP gene may be expected to lead to decreased endothelial nitric oxide production.…”

Section: Said Et Al Pulmonary Arterial Hypertension In Vip Ko Micementioning

confidence: 99%

Moderate Pulmonary Arterial Hypertension in Male Mice Lacking the Vasoactive Intestinal Peptide Gene

et al. 2007

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Background-Vasoactive intestinal peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, has been reported absent in pulmonary arteries from patients with idiopathic pulmonary arterial hypertension (PAH). We have tested the hypothesis that targeted deletion of the VIP gene may lead to PAH with pulmonary vascular remodeling. Methods and Results-We examined VIP knockout (VIP Ϫ/Ϫ ) mice for evidence of PAH, right ventricular (RV) hypertrophy, and pulmonary vascular remodeling. Relative to wild-type control mice, VIP Ϫ/Ϫ mice showed moderate RV hypertension, RV hypertrophy confirmed by increased ratio of RV to left ventricle plus septum weight, and enlarged, thickened pulmonary artery and smaller branches with increased muscularization and narrowed lumen. Lung sections also showed perivascular inflammatory cell infiltrates. No systemic hypertension and no arterial hypoxemia existed to explain the PAH. The condition was associated with increased mortality. Both the vascular remodeling and RV remodeling were attenuated after a 4-week treatment with VIP. Conclusions-Deletion of the VIP gene leads to spontaneous expression of moderately severe PAH in mice during air breathing.Although not an exact model of idiopathic PAH, the VIP Ϫ/Ϫ mouse should be useful for studying molecular mechanisms of PAH and evaluating potential therapeutic agents. VIP replacement therapy holds promise for the treatment of PAH, and mutations of the VIP gene may be a factor in the pathogenesis of idiopathic PAH. (Circulation.

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“…When including any wheeze and chronic cough in the preceding list of symptoms, as VAN DEN NIEUWENHOF et al [1] did, AHR at baseline remained significantly associated with asthma incidence among children (OR 3.18, 95% CI 1.08-9.37, n5142), adults (OR 2.84, 95% CI 1.08-7.42, n5343), or those aged 10-22 yrs (OR 3.27, 95% CI 1.11-9.69, n5149). Furthermore, when asymptomatic adult subjects where defined by the absence of chronic cough, chronic phlegm, dyspnoea or wheezing, as per BRUTSCHE et al [6] in the SAPALDIA study, AHR was also associated with asthma incidence (OR 2.40, 95% CI 1.06-5.49, n5387).…”

Section: To the Editorsmentioning

confidence: 87%

“…Beyond their presence together in the same neurons, VIP and NO have the following close functional interactions. 1) VIP promotes the normal synthesis and functioning of endothelial NOS, by stimulation of tetrahydrobiopterin, which plays a pivotal role in NOS function [6]. 2) VIP activates a constitutive form of neuronal NOS and NO mediates a significant proportion of VIP-induced tracheal relaxation.…”

Section: Animal Models Of Airway Hyperresponsivenessmentioning

confidence: 99%

Animal models of airway hyperresponsiveness

Said¹

2008

Eur Respir J

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Vasoactive intestinal peptide induces both tyrosine hydroxylase activity and tetrahydrobiopterin biosynthesis in PC12 cells

Cited by 22 publications

References 74 publications

Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion: Table 1—

Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion: Table 1—

Moderate Pulmonary Arterial Hypertension in Male Mice Lacking the Vasoactive Intestinal Peptide Gene

Animal models of airway hyperresponsiveness

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