Bad blood, bad endothelium: ill fate?

Yoder, Mervin C.; Rounds, Sharon

doi:10.1182/blood-2011-02-332643

Cited by 8 publications

(4 citation statements)

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“…43 Other data highlight a potential interdependence of dysregulated hematopoiesis and abnormal pulmonary vascular endothelial behavior that may play a key role in the development of PAH. 10 It was previously demonstrated that cells from the mononuclear lineage could differentiate into endothelial and SMC-like cells at injured vessels, [44][45][46][47] and that circulating precursors of this lineage can contribute to hypoxia-induced pulmonary vascular remodeling. 6 In this context, a stimulus-dependent generation of proangiogenic and BM-derived early progenitors could be required for physiologic repair response to ongoing pulmonary vascular shear stress and endothelial injury.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7][8] However, it is unclear, whether this entry of progenitors represents a protective or a worsening process in the development of PAH. 9 Other observations have also identified an association between PAH and BMrelated hematologic disorders 10 : in proliferative disorders of the hematopoietic stem cells such as myeloproliferative cancers, there is an unexplained high incidence of PAH. PAH is now a recognized complication of BM transplantation for leukemia, 11 chronic myeloproliferative disorders, 12 or in the treatment of malignant infantile osteopetrosis.…”

Section: Introductionmentioning

confidence: 99%

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Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Launay

Hervé

Crinon

et al. 2012

Blood

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Pulmonary arterial hypertension (PAH) is IntroductionPulmonary arterial hypertension (PAH) is a rare but fatal disease, often of unknown origin, characterized by progressive increase in pulmonary vascular resistance and remodeling associated with vasoconstriction. 1 PAH is histologically characterized by a neomuscularization of small pulmonary arteries with intimal thickening, medial hypertrophy, adventitial proliferation, and abnormal extracellular matrix deposition. The progression of vascular remodeling results in vascular lumen narrowing, increased pulmonary artery resistance, hypoxia, and right heart hypertrophy, although the molecular pathways initiating this remodeling are not clearly established.On the one hand, stem cells, resident or not, may give rise to a significant proportion of differentiating/proliferating smooth muscle cells (SMCs) that contribute to intimal hyperplasia in lung vascular remodeling. 2 Moreover, genetic ablation of the transmembrane tyrosine kinase receptor for stem cell factor/c-kit pathway results in a marked reduction in intimal hyperplasia in animal models of vascular injury; conversely, wild-type (WT) bone marrow (BM) reconstitution in c-kit mutant mice led to intimal hyperplasia comparable with WT animals. 3 Pharmacologic antagonism of the c-kit pathway with STI-571 (imatinib mesylate; Gleevec) also results in a marked reduction in hyperplasia. 3 Mobilization of c-kit expressing cells from BM to blood circulation is a physiologic response to hypoxia. Increasing evidence supports the idea that these progenitor cells of BM origin may also contribute to vascular wall remodeling that is characteristic of PAH. [4][5][6][7][8] However, it is unclear, whether this entry of progenitors represents a protective or a worsening process in the development of PAH. 9 Other observations have also identified an association between PAH and BMrelated hematologic disorders 10 : in proliferative disorders of the hematopoietic stem cells such as myeloproliferative cancers, there is an unexplained high incidence of PAH. PAH is now a recognized complication of BM transplantation for leukemia, 11 chronic myeloproliferative disorders, 12 or in the treatment of malignant infantile osteopetrosis. 13 On the other hand, serotonin (5-hydroxytryptamine ) is associated with the pathogenesis of PAH. 14 Therapeutic drugs with PAH as a side effect, such as the amphetamine derivative and anorexigen dexfenfluramine, are potent 5-HT releasers acting at 5-HT transporter (SERT) and/or agonists at 5-HT receptors (5-HTRs). 15 An over-expression of 5-HT 2B Rs is observed in PAH. 16 Blockade of 5-HT 2B Rs using independent approaches, either genetic (5-HT 2B R knock-out mice; 5-HT 2B Ϫ/Ϫ ) or pharmacologic (5-HT 2B antagonist RS-12744) inactivation, completely prevented the development of hypoxia-induced pulmonary hypertension in mice. 16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduc...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Launay

Hervé

Crinon

et al. 2012

Blood

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“…On ne savait pas, cependant, si cette présence de progéniteurs représente une protection ou un processus d'aggravation du développement de l'HTAP (Diller et al, 2010). D'autres observations ont également identifié une association entre l'HTAP et des troubles hématologiques liés à la moelle osseuse (Yoder & Rounds, 2011): dans les troubles de prolifération des cellules souches hématopoïétiques tels que les cancers myéloprolifératifs, il y a une incidence élevée et inexpliquée d'HTAP. L'HTAP est maintenant reconnue comme une complication des transplantations de moelle osseuse lors du traitement de certaines leucémies (Limsuwan et al, 2006), des troubles myéloprolifératifs chroniques (Farha et al, 2011), ou du traitement de l'ostéopétrose maligne infantile (Steward et al, 2004).…”

Section: Htap Et Facteurs Hématopoïétiques Extrinsèques Aux Poumonsunclassified

Hypertension artérielle pulmonaire, moelle osseuse, précurseurs endothéliaux et sérotonine

Ayme-Dietrich

Banas

Monassier

et al. 2016

Biologie Aujourd'hui

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Serotonin and bone-marrow-derived stem cells participate together in triggering pulmonary hypertension. Our work has shown that the absence of 5-HT2B receptors generates permanent changes in the composition of the blood and bone-marrow in the myeloid lineages, particularly in endothelial cell progenitors. The initial functions of 5-HT2B receptors in pulmonary arterial hypertension (PAH) are restricted to bone-marrow cells. They contribute to the differentiation/proliferation/mobilization of endothelial progenitor cells from the bone-marrow. Those bone-marrow-derived cells have a critical role in the development of pulmonary hypertension and pulmonary vascular remodeling. These data indicate that bone-marrow derived endothelial progenitors play a key role in the pathogenesis of PAH and suggest that interactions involving serotonin and bone morphogenic protein type 2 receptor (BMPR2) could take place at the level of the bone-marrow.

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“…When the extent of EC loss is such small, i.e. limited to a belt of cells around the whole circumference of the arterial vessel, the re-endothelization process is driven by proliferation, spreading, and migration of surviving ECs into the damaged site [4]. On the other hand, larger areas of injury may release chemical messages, such as concentration gradients of vascular endothelial growth factor (VEGF) and stromal derived factor-1α (SDF-1α), that recruit circulating endothelial progenitor cells to the wound edge in order to replace damaged endothelium [5-10].…”

Section: Introductionmentioning

confidence: 99%

Ca2+-dependent nitric oxide release in the injured endothelium of excised rat aorta: a promising mechanism applying in vascular prosthetic devices in aging patients

et al. 2013

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BackgroundNitric oxide is key to endothelial regeneration, but it is still unknown whether endothelial cell (EC) loss results in an increase in NO levels at the wound edge. We have already shown that endothelial damage induces a long-lasting Ca2+ entry into surviving cells though connexin hemichannels (CxHcs) uncoupled from their counterparts on ruptured cells. The physiological outcome of injury-induced Ca2+ inflow is, however, unknown.MethodsIn this study, we sought to determine whether and how endothelial scraping induces NO production (NOP) in the endothelium of excised rat aorta by exploiting the NO-sensitive fluorochrome, DAF-FM diacetate and the Ca2+-sensitive fluorescent dye, Fura-2/AM.ResultsWe demonstrated that injury-induced NOP at the lesion site is prevented in presence of the endothelial NO synthase inhibitor, L-NAME, and in absence of extracellular Ca2+. Unlike ATP-dependent NO liberation, the NO response to injury is insensitive to BTP-2, which selectively blocks store-operated Ca2+ inflow. However, injury-induced NOP is significantly reduced by classic gap junction blockers, and by connexin mimetic peptides specifically targeting Cx37Hcs, Cx40HCs, and Cx43Hcs. Moreover, disruption of caveolar integrity prevents injury-elicited NO signaling, but not the accompanying Ca2+ response.ConclusionsThe data presented provide the first evidence that endothelial scraping stimulates NO synthesis at the wound edge, which might both exert an immediate anti-thrombotic and anti-inflammatory action and promote the subsequent re-endothelialization.

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Bad blood, bad endothelium: ill fate?

Cited by 8 publications

References 8 publications

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Hypertension artérielle pulmonaire, moelle osseuse, précurseurs endothéliaux et sérotonine

Ca2+-dependent nitric oxide release in the injured endothelium of excised rat aorta: a promising mechanism applying in vascular prosthetic devices in aging patients

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