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

Said, Sami I.; Hamidi, Sayyed A.; Dickman, Kathleen G.; Szema, Anthony M.; Lyubsky, Sergey; Lin, Richard Z.; Jiang, Yaping; Chen, John J.; Waschek, James A.; Kort, Smadar

doi:10.1161/circulationaha.106.681718

Cited by 155 publications

(127 citation statements)

References 45 publications

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“…Preclinical and open-label studies in humans support a role for vasoactive intestinal peptide (VIP) in the regulation of pulmonary vascular homeostasis (Leuchte et al, 2008;Petkov et al, 2003;Saga & Said, 1984;Said et al, 2007). VIP is a 28 amino acid peptide that has been shown to relax pulmonary vascular smooth muscle in several mammalian species in vitro (Saga & Said, 1984) and inhibits proliferation of pulmonary vascular smooth muscle cells from patients with PAH (Petkov et al, 2003).…”

Section: Vasoactive Intestinal Peptide (Aviptadil)mentioning

confidence: 99%

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

Lythgoe

Rhodes

Ghataorhe

et al. 2016

Pharmacology & Therapeutics

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The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). But against this backdrop there have been some notable disappointments in drug development. Here we use these as case studies to emphasise the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies and the value of deep-phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of 'omics' technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.

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Section: Vasoactive Intestinal Peptide (Aviptadil)mentioning

confidence: 99%

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

Lythgoe

Rhodes

Ghataorhe

et al. 2016

Pharmacology & Therapeutics

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“…-/-mice and immunity The targeted removal of the VIP gene has been engineered [64][65][66][67][68] . A cadre of studies marshaled by James Waschek and other colleagues has focused on pulmonary disorders and asthma.…”

Section: Vipmentioning

confidence: 99%

Vasoactive intestinal peptide signaling axis in human leukemia

Dorsam

Benton²,

Failing³

et al. 2011

WJBC

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The vasoactive intestinal peptide (VIP) signaling axis constitutes a master "communication coordinator" between cells of the nervous and immune systems. To date, VIP and its two main receptors expressed in T lymphocytes, vasoactive intestinal peptide receptor (VPAC)1 and VPAC2, mediate critical cellular functions regulating adaptive immunity, including arresting CD4 T cells in G1 of the cell cycle, protection from apoptosis and a potent chemotactic recruiter of T cells to the mucosa associated lymphoid compartment of the gastrointestinal tissues. Since the discovery of VIP in 1970, followed by the cloning of VPAC1 and VPAC2 in the early 1990s, this signaling axis has been associated with common human cancers, including leukemia. This review highlights the present day knowledge of the VIP ligand and its receptor expression profile in T cell leukemia and cell lines. Also, there will be a discussion describing how the anti-leukemic DNA binding transcription factor, Ikaros, regulates VIP receptor expression in primary human CD4 T lymphocytes and T cell lymphoblastic cell lines (e.g. Hut-78). Lastly, future goals will be mentioned that are expected to uncover the role of how the VIP signaling axis contributes to human leukemogenesis, and to establish whether the VIP receptor signature expressed by leukemic blasts can provide therapeutic and/or diagnostic information.

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“…7,8 Murine susceptibility to chronic hypoxic PHTN depends on genetic background. 5 Additionally, inflammation due to viral infection, hypoxia, or other forms of injury is important.…”

mentioning

confidence: 99%

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

Dempsey

Wick

Karoor³

et al. 2009

The American Journal of Pathology

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Neprilysin is a transmembrane metalloendopeptidase that degrades neuropeptides that are important for both growth and contraction. In addition to promoting carcinogenesis, decreased levels of neprilysin increases inflammation and neuroendocrine cell hyperplasia, which may predispose to vascular remodeling. Early pharmacological studies showed a decrease in chronic hypoxic pulmonary hypertension with neprilysin inhibition. We used a genetic approach to test the alternate hypothesis that neprilysin depletion increases chronic hypoxic pulmonary hypertension. Loss of neprilysin had no effect on baseline airway or alveolar wall architecture, vessel density, cardiac function, hematocrit, or other relevant peptidases. Only lung neuroendocrine cell hyperplasia and a subtle neuropeptide imbalance were found. After chronic hypoxia, neprilysin-null mice exhibited exaggerated pulmonary hypertension and striking increases in muscularization of distal vessels. Subtle thickening of proximal media/adventitia not typically seen in mice was also detected. In contrast, adaptive right ventricular hypertrophy was less than anticipated. Hypoxic wild-type pulmonary vessels displayed close temporal and spatial relationships between decreased neprilysin and increased cell growth. Smooth muscle cells from neprilysin-null pulmonary arteries had increased proliferation compared with controls, which was decreased by neprilysin replacement. These data suggest that neprilysin may be protective against chronic hypoxic pulmonary hypertension in the lung, at least in part by attenuating the growth of smooth muscle cells. Lung-targeted strategies to increase neprilysin levels could have therapeutic benefits in the treatment of this disorder. Chronic hypoxic pulmonary hypertension (PHTN) is a major clinical problem, complicating most lung and heart disorders. 1,2 In large animal models of chronic hypoxic PHTN that closely resemble human disease, the earliest pulmonary artery (PA) smooth muscle cell (SMC) proliferative changes occur at the medial/adventitial border. 3 Growth and migration of SMC and myofibroblasts in distal vessels is also a prominent feature. 4,5 These structural changes, together with derangements in vascular tone, are major contributors to the severity of chronic hypoxic PHTN. [1][2][3][4][5][6] However, mechanisms that regulate susceptibility to, and severity of, chronic hypoxic PHTN and vascular remodeling remain poorly understood. Currently available treatments for chronic hypoxic PHTN are also inadequate.

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

Cited by 155 publications

References 45 publications

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

Vasoactive intestinal peptide signaling axis in human leukemia

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

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