Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress–mediated vasodilation

Belhassen, Laurent; Pelle, Gabriel; Sediame, Saı̈d; Bachir, Dora; Carville, Claudine; Bucherer, C.; Lacombe, Catherine; Galactéros, Frédéric; Adnot, Serge

doi:10.1182/blood.v97.6.1584

Cited by 176 publications

(162 citation statements)

References 31 publications

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“…We found that methacholine-induced forearm blood flow response was preserved in HbSS, while others have demonstrated a heightened response to acetylcholine [7,9]. The reasons for these apparently discrepant findings are not immediately clear, but could relate to differences in the study populations.…”

Section: Discussioncontrasting

confidence: 55%

“…Transgenic murine models of sickle cell disease have shown greater basal NO production with a greater rise in blood pressure with NOS inhibition, although results regarding NOS expression are controversial [5,6]. In humans with HbSS, the contribution of NO to increased basal flow and reduced peripheral resistance is unclear [7]. Our findings of greater resting forearm blood flow with greater absolute and relative flow decreases with NOS inhibition supports increased basal NO production contributes to the regulation of basal tone and tissue perfusion in HbSS in the steady state.…”

Section: Discussionmentioning

confidence: 99%

“…However, in humans with HbSS, there is controversy regarding microvascular dysfunction of the resistance vessel of the forearm. Belhassen et al [7] found preserved responses to endogenous and exogenous NO vasodilators, while Reiter et al [8] suggested diminished NO bioavailability in HbSS.…”

Section: Discussionmentioning

confidence: 99%

“…In experimental models, despite increased NO production and perhaps NOS (NO synthase) expression, the response to endothelium-dependent vasodilators is impaired in both micro-and macrocirculations [4][5][6]. In humans with HbSS, abnormalities of endothelium-dependent vasodilation in conduit vessels has been reported; however, uncertainty remains regarding resistance vessel response to NO-mediated vasodilators [7][8][9]. Despite these recent findings, vascular function and NO bioactivity in peripheral conduit and resistance vessels in HbSS remain incompletely defined.…”

Section: Introductionmentioning

confidence: 99%

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Sickle cell anemia is associated with reduced nitric oxide bioactivity in peripheral conduit and resistance vessels

et al. 2003

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The purpose of the study was to examine endothelium-dependent and -independent vasodilation of conduit and resistance vessels in sickle cell anemia (HbSS). We measured the effects of intra-arterial infusion of methacholine, sodium nitroprusside, and N G -monomethyl-L-arginine (L-NMMA) on forearm blood flow using venous occlusion plethysmography in eight patients with HbSS and 11 HbAA controls. We assessed vasodilation of the conduit brachial artery using ultrasound in 17 patients with HbSS and 41 nonanemic controls. Forearm blood flow response to methacholine was similar in HbSS and HbAA, while the response to sodium nitroprusside was greater in those with HbSS. Nitric oxide synthase inhibition with L-NMMA attenuated methacholine-induced forearm blood flow to a lesser extent in HbSS compared to HbAA, suggesting diminished nitric oxide (NO) contribution to endothelium-dependent vasodilation. Flow-mediated and nitroglycerin-induced dilation were impaired in HbSS compared to controls and were not affected by the antioxidant vitamin C or the precursor substrate for NO synthesis L-arginine. NO bioactivity is reduced but differs in peripheral conduit and resistance vessels in HbSS. Resistance vessels have preserved response to exogenous NO donors but have diminished contribution of NO to endothelium-dependent vasodilation. Conduit vessels demonstrate impaired vasodilation to endogenous and exogenous NO. Am.

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sickle cell anemia is associated with reduced nitric oxide bioactivity in peripheral conduit and resistance vessels

et al. 2003

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“…The relevance of these data, of course, lies in the fact that humans with sickle disease are known to be biodeficient in NO [13,14]. Thus, the implication of this study is that the NO-deficient status of patients with sickle cell anemia, in the context of their already existing inflammatory state [7], probably increases their risk for coagulation activation, TF being the trigger of such activation.…”

Section: Discussionmentioning

confidence: 77%

Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

et al. 2009

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Activation of the coagulation system is a characteristic feature of sickle cell anemia, which also includes clinical thrombosis. The sickle transgenic mouse abnormally expresses tissue factor (TF) on the pulmonary vein endothelium. Knowing that this aberrancy is stimulated by inflammation, we sought to determine whether nitric oxide (NO) contributes to regulation of endothelial TF expression in the sickle mouse model. We used the NY1DD sickle mouse, which exhibits a low-TF to high-TF phenotype switch on exposure to hypoxia/reoxygenation. Manipulations of NO biology, such as breathing NO or addition of arginine or L-NAME (N-nitro-L-arginine-methyl-ester) to the diet, caused significant modulations of TF expression. This was also seen in hBERK1 sickle mice, which have a different genetic background and already have high-TF even at ambient air. Study of NY1DD animals bred to overexpress endothelial nitric oxide synthase (eNOS; eNOSTg) or to have an eNOS knockout state (one eNOS 2/2 animal and several eNOS 1/2 animals) demonstrated that eNOS modulates endothelial TF expression in vivo by down-regulating it. Thus, the biodeficiency of NO characteristic of patients with sickle cell anemia may heighten risk for activation of the coagulation system. Am. J. Hematol. 85:41-45, 2010. V

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Preliminary Assessment of Inhaled Nitric Oxide for Acute Vaso-occlusive Crisis in Pediatric Patients With Sickle Cell Disease

Weiner¹,

Hibberd²,

Betit³

et al. 2003

JAMA

167

100

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ASO-OCCLUSION IS ONE OF THE hallmarks and major complications of sickle cell disease (SCD), resulting in acute debilitating episodic pain and contributing to infection, acute chest syndrome, splenic sequestration, stroke, acute and chronic multisystem organ damage, and shortened life expectancy. Acute painful vaso-occlusive crisis (VOC) is one of the earliest manifestations of SCD, with crises often beginning in infancy. 1,2 Beyond early childhood, VOC accounts for 90% of hospitalizations in children with SCD. The pathophysiology of vasoocclusion is complex and not fully understood. Polymerization of deoxygenated hemoglobin S (HbS) produces sickled cells that result in vasoocclusion. In addition, abnormal interactions between poorly deformable HbS and vascular endothelium result in dysregulation of vascular tone 3-5 ; activation of monocytes, 6 adhesion molecules, 7 and procoagulant factors 8 ; and reperfusion injury. 9 These vascular disturbances increase red blood cell transit time, prolonging deoxygenation, which promotes further sickling and vaso-occlusion. Despite advances in understanding of SCD including identification of potential targets for therapy, to date there are no effective, approved mechanismof-disease-based therapies for acute VOC, and symptom-directed therapies (ie, analgesia and fluids) with

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Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress–mediated vasodilation

Cited by 176 publications

References 31 publications

Sickle cell anemia is associated with reduced nitric oxide bioactivity in peripheral conduit and resistance vessels

Sickle cell anemia is associated with reduced nitric oxide bioactivity in peripheral conduit and resistance vessels

Endothelial nitric oxide synthase and nitric oxide regulate endothelial tissue factor expression in vivo in the sickle transgenic mouse

Preliminary Assessment of Inhaled Nitric Oxide for Acute Vaso-occlusive Crisis in Pediatric Patients With Sickle Cell Disease

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