ABSTRACT
Kasabach-Merritt phenomenon can be encountered in the perinatal period. No consensus exists regarding prenatal management. We report one prenatal case leading to therapeutic abortion and one neonatal case, successfully treated by a multimodal therapy. Prenatal counseling should include the possibility of neonatal multimodal treatment that can lead to favorable outcomes.
ABSTRACT
Vascular remodeling associated with increased blood flow involves reactive oxygen species (ROS)-dependent activation of matrix metalloproteinases (MMPs). To investigate the potential role of NF-kappaB in this process, human umbilical vein endothelial cells were subjected to different flow conditions during a 24-h period. Normal (15 dynes/cm(2)) and high (30 dynes/cm(2)) shear stress induced IkappaBalpha degradation and NF-kappaB p65 phosphorylation, and activated MMP-2 and MMP-9. These effects were blunted in cells incubated with the NF-kappaB inhibitor pyrrolidine dithio-carbamate (PDTC). In mice, creation of a carotid artery-jugular vein arteriovenous fistula (AVF) increased carotid blood flow sixfold, triggering the increase in carotid diameter from 459 +/- 8 microm (before AVF) to 531 +/- 13 and 669 +/- 21 microm (7 and 21 days after AVF). ROS production and NF-kappaB activity were enhanced in fistulated carotids, but only the latter was blocked by PDTC, although PDTC blocked ROS production in vitro. In PDTC-treated mice, changes in carotid caliber and shear stress matched controls at 7 days, but carotids enlarged only marginally thereafter, reaching only 578 +/- 8 microm at 21 days (p < 0.01 vs. untreated). Similarly, both MMP-9 expression and activity were abrogated by PDTC at 3 weeks. Hence, induction of NF-kappaB by shear stress contributes to MMP induction and allows long-term flow-induced vascular enlargement.
Subject(s)
Blood Vessels/anatomy & histology , NF-kappa B/physiology , Animals , Blood Vessels/drug effects , Blood Vessels/enzymology , Blood Vessels/metabolism , Cells, Cultured , Matrix Metalloproteinases/metabolism , Mice , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Phosphorylation , Pyrrolidines/pharmacology , Reactive Oxygen Species/metabolism , Thiocarbamates/pharmacologyABSTRACT
Hypertension is a known risk factor for the development of atherosclerosis. To assess how mechanical factors contribute to this process, mouse carotid arteries were maintained in organ culture at normal (80 mm Hg) or high (150 mm Hg) intraluminal pressure for 1, 6, 12, or 24 hours. Thereafter, fluorescent human monocytic cells (U937) were injected intraluminally and allowed to adhere for 30 minutes before washout. U937 adhesion was increased in vessels kept at 150 mm Hg 12 hours (23.5+/-5.7 versus 9.9+/-2.2 cells/mm at 80 mm Hg; P<0.05) or 24 hours (26.7+/-5.7 versus 8.8+/-1.5 cells/mm; P<0.05). At 24 hours, high pressure was associated with increased mRNA expression of monocyte chemoattractant protein-1, interleukin-6, keratinocyte-derived chemokine, and vascular cell adhesion molecule-1 (6.9+/-2.1, 4.4+/-0.1, 9.8+/-2.8, and 2.4+/-0.1-fold respectively; P<0.05), as assessed by quantitative RT-PCR and corroborated by immunohistochemistry, which also revealed an increase in intracellular adhesion molecule-1 expression. Nuclear factor kappaB inhibition using SN50 peptide abolished the overexpression of chemokines and adhesion molecules and reduced U937 adhesion in vessels at 150 mm Hg. Moreover, treatment of vessels and cells with specific neutralizing antibodies established that monocyte chemoattractant protein-1, interleukin-6, and keratinocyte-derived chemokine released from vessels at 150 mm Hg primed the monocytes, increasing their adhesion to vascular cell adhesion molecule-1 but not intracellular adhesion molecule-1 via alpha4beta1 integrins. The additive effect of chemokines on the adhesion of U937 cells to vascular cell adhesion molecule-1 was confirmed by in vitro assay. Finally, pressure-dependent U937 adhesion was blunted in arteries from mice overexpressing endothelial NO synthase. Hence, high intraluminal pressure induces cytokine and adhesion molecule expression via nuclear factor kappaB, leading to monocytic cell adhesion. These results indicate that hypertension may directly contribute to the development of atherosclerosis through nuclear factor kappaB induction.
