PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin

Bajou, Khalid; Herkenne, Stéphanie; Thijssen, Victor L.; D’Amico, Salvino; Nguyen, Ngoc-Quynh-Nhu; Bouché, Ann; Tabruyn, Sébastien P.; Srahna, Mohammed; Carabin, Jean-Yves; Nivelles, Olivier; Paques, Cécile; Cornelissen, Ivo; Lion, Michelle; Noël, Agnès; Gils, Ann; Vinckier, Stefan; Declerck, Paul; Griffioen, Arjan W.; Dewerchin, Mieke; Martial, Joseph; Carmeliet, Peter; Struman, Ingrid

doi:10.1038/nm.3552

Cited by 92 publications

(75 citation statements)

References 49 publications

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“…Thus, PAI-1 and iNOS are downstream of 16-kDa prolactin but not of full-length prolactin (12)(13)(14). The 16-kDa form, but not the full-length form, requires the formation of a complex with PAI-1 to be active (41), and their intracellular signaling pathways differ (42).…”

Section: Discussionmentioning

confidence: 99%

Prolactin alters blood pressure by modulating the activity of endothelial nitric oxide synthase

Chang

Grant

Tomita

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Increased levels of a cleaved form of prolactin (molecular weight 16 kDa) have been associated with preeclampsia. To study the effects of prolactin on blood pressure (BP), we generated male mice with a single-copy transgene (Tg; inserted into the hypoxanthineguanine phosphoribosyltransferase locus) that enables inducible hepatic production of prolactin and its cleavage product. The Tg is driven by the indole-3-carbinol (I3C)-inducible rat cytochrome P450 1A1 promoter. When the Tg mice were fed normal chow (NC), plasma prolactin concentrations were comparable to those in female WT mice in the last third of pregnancy, and BP was lower than in WT mice (∼95 mm Hg vs. ∼105 mm Hg). When the Tg mice were fed chow containing IC3, plasma prolactin concentrations increased threefold, BP increased to ∼130 mm Hg, and cardiac function became markedly impaired. IC3 chow did not affect the WT mice. Urinary excretion of nitrite/nitrate and the amount of Ser1177-phosphorylated endothelial nitric oxide (NO) synthase (eNOS) were significantly greater in the Tg mice fed NC than in WT mice, as they are during pregnancy. However, when I3C was fed, these indicators of NO production became significantly less in the Tg mice than in WT mice. The effects of increased plasma prolactin were abolished by a genetic absence of eNOS. Thus, a threefold increase in plasma prolactin is sufficient to increase BP significantly and to markedly impair cardiac function, with effects mediated by NO produced by eNOS. We suggest that pregnant women with abnormally high prolactin levels may need special attention.hypertension | lactation | protein kinase B/Akt P rolactin, a 23-kDa polypeptide hormone, is a potent multifunctional cytokine with a broad range of biological effects, including water and salt balance, lactogenesis, cell proliferation and differentiation, testicular Leydig cell function, T-cell immunity, pancreatic β-cell function, hematopoiesis, and adipogenesis (1). Prolactin is physiologically secreted mainly from the anterior lobe of pituitary gland. The secretion is negatively regulated by dopamine and positively regulated by prolactin-releasing peptide (2) synthesized in the hypothalamus. The levels of prolactin in the serum, urine, and amniotic fluids are significantly higher in patients with preeclampsia than in subjects with normal pregnancy (3-5), suggesting that prolactin is involved in the pathogenesis of pregnancy-associated hypertension. However, animal experiments have shown inconsistent effects of prolactin on blood pressure (BP). Thus, acute i.v. infusion of prolactin increased BP in rabbits (6), but, when ovine prolactin was chronically given i.p. via an osmotic minipump in rats, BP was decreased (7). It has also been reported that chronic prolactin infusion caused an increase in urinary sodium, potassium, and water excretion, but no significant changes in arterial pressure, in rats (8).To study the chronic effects of different plasma concentrations of prolactin on BP and general well-being, we have generated male mice with a si...

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Section: Discussionmentioning

confidence: 99%

Prolactin alters blood pressure by modulating the activity of endothelial nitric oxide synthase

Chang

Grant

Tomita

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…44,104 They showed that 16-kDa prolactin induces endothelial cells to package miR-146a into exosomes, small lipid-encapsulated particles, which are then secreted and taken up by cardiomyocytes. The miR-146a internalized into cardiomyocytes then suppresses the neuregulin/ErbB pathway, thereby promoting cardiomyocyte apoptosis.…”

Section: The Vasculo-hormonal Hypothesismentioning

confidence: 99%

Peripartum Cardiomyopathy

2016

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Abstract-Peripartum cardiomyopathy is a potentially life-threatening pregnancy-associated disease that typically arises in the peripartum period and is marked by left ventricular dysfunction and heart failure. The disease is relatively uncommon, but its incidence is rising. Women often recover cardiac function, but long-lasting morbidity and mortality are not infrequent. Management of peripartum cardiomyopathy is largely limited to the same neurohormonal antagonists used in other forms of cardiomyopathy, and no proven disease-specific therapies exist yet. Research in the past decade has suggested that peripartum cardiomyopathy is caused by vascular dysfunction, triggered by late-gestational maternal hormones. Most recently, information has also indicated that many cases of peripartum cardiomyopathy have genetic underpinnings. We review here the known epidemiology, clinical presentation, and management of peripartum cardiomyopathy, as well as the current knowledge of the pathophysiology of the disease.

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“…Consistent with their ability to block the neuronal activation of the MAPK/ERK1/2 and PI3K/AKT pathways by VEGF and NGF, vasoinhibins are known to inhibit the action of several vasoactive substances including VEGF and basic fibroblast growth factor [48][49][50], and to activate protein phosphatase 2A in endothelial cells [49]. Vasoinhibins bind to a multicomponent complex formed by plasminogen activator inhibitor-1, urokinase plasminogen activator, and the urokinase plasminogen activator receptor on endothelial cells, which leads to the perturbation of signaling pathways triggered by angiogenic factors like VEGF, including MAPK/ERK [51]. Vasoinhibins also inhibit VEGF-and basic fibroblast growth factor-induced activation of the Ras-Raf-MAPK pathway [52,53], the Ras-Tiam1-Rac1-Pak1 pathway [54], and the Ca 2+ / calmodulin-mediated activation of endothelial nitric oxide synthase [50].…”

Section: Discussionmentioning

confidence: 99%

Vasoinhibin Suppresses the Neurotrophic Effects of VEGF and NGF in Newborn Rat Primary Sensory Neurons

et al. 2017

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Background/Aims: Studies on the biological actions of vasoinhibins have focused mainly on endothelial cells. However, there is incipient knowledge about how vasoinhibins affect the nervous system, even if the target cells and mechanisms of action involved in these effects are unknown. Methods: In order to determine if neurons are direct targets of vasoinhibins, we examined cellular outcomes and the intracellular pathways involved in the neuronal actions of vasoinhibins using newborn rat dorsal root ganglion (DRG) neurons as a model system. Results: Vascular endothelial growth factor (VEGF) or nerve growth factor (NGF) treatment for 48 h resulted in neurite outgrowth stimulation in both DRG cultured explants and isolated primary sensory neurons. Interestingly, a recombinant vasoinhibin containing the first 123 amino acids of human prolactin antagonized the VEGF- and NGF-induced stimulation of neurite outgrowth. Vasoinhibin significantly reduced the density of neurites in DRG explants and obliterated neuritogenesis in isolated DRG neurons in primary culture, supporting a direct neuronal effect of vasoinhibin. In cultures of isolated DRG cells, virtually all β3-tubulin-labeled cells express TrkA, and the majority of these cells also express VEGFR2. Short-term VEGF or NGF treatment of DRG explants resulted in increased ERK1/2 and AKT phosphorylation, whereas incubation of DRG with the combination of either VEGF or NGF together with vasoinhibin resulted in blunted VEGF- or NGF-induced phosphorylation of both ERK1/2 and AKT. Conclusion: Our results show that primary sensory neurons are direct targets of vasoinhibin, and suggest that vasoinhibin inhibition of neurite outgrowth involves the disruption of ERK and AKT phosphorylation cascades.

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PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin

Cited by 92 publications

References 49 publications

Prolactin alters blood pressure by modulating the activity of endothelial nitric oxide synthase

Prolactin alters blood pressure by modulating the activity of endothelial nitric oxide synthase

Peripartum Cardiomyopathy

Vasoinhibin Suppresses the Neurotrophic Effects of VEGF and NGF in Newborn Rat Primary Sensory Neurons

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