Doxycycline Modulates Smooth Muscle Cell Growth, Migration, and Matrix Remodeling after Arterial Injury

Bendeck, Michelle P.; Conte, Michelle; Zhang, Mingyu; Nili, Nafiseh; Strauss, Bradley H.; Farwell, Stephanie M.

doi:10.1016/s0002-9440(10)64929-2

Cited by 183 publications

(141 citation statements)

References 42 publications

(47 reference statements)

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“…This is in line with studies showing prevention of blood flow-induced artery enlargement 31 and inhibition of several phases of intimal thickening after arterial injury. 32 In contrast to results obtained in large arteries, doxycycline treatment did not modify vascular remodeling in mesenteric arteries, suggesting that despite the increase of MMP-2 activity, this family of enzymes does not appear to be necessary for the eutrophic remodeling process to occur. Interestingly, doxycycline appeared to influence small artery "hypertrophy," although it is not a main feature in this model.…”

Section: Bouvet Et Al Matrix Changes During Eutrophic Remodelingmentioning

confidence: 56%

Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition

et al. 2005

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Abstract-In essential hypertension, conduit arteries present hypertrophic remodeling (increased cross-sectional area), whereas small arteries undergo eutrophic remodeling. The involvement of matrix metalloproteinases (MMPs) and de-adhesion proteins, such as tenascin-C and thrombospondin, has been relatively well characterized in large artery remodeling, but their contribution is not known in small artery remodeling. Rats received N -nitro-L-arginine methyl ester (L-NAME; 50 mg/kg per day) in their drinking water on days 1, 3, 7, 14, and 28. Arterial MMP-2 activity was measured by ELISA, whereas levels of tenascin-C and thrombospondin were assessed by Western blotting. To determine the involvement of MMPs, additional L-NAME rats received the nonselective MMP inhibitor doxycycline (30 mg/kg per day) on days 7, 14, and 28. Already, at day 1, pressure was elevated. Media/lumen ratio of mesenteric arteries and the aorta increased gradually to reach significance at 28 days. However, the cross-sectional area increased only in the aorta, confirming the heterogeneous remodeling process. In small arteries, MMP-2 activity increased after 7 and 14 days of treatment and returned to baseline at 28 days, whereas the elevation was more progressive but sustained in the aorta. The level of thrombospondin paralleled that of MMP-2 in small arteries, whereas tenascin-C levels declined rapidly and stayed below control values. Doxycycline blunted large artery remodeling but had no influence on the development of eutrophic remodeling despite elevation of MMP-2 activity in the process. Thus, in contrast to large artery hypertrophic remodeling, in which the contributions of cellular de-adhesion and matrix breakdown is manifest, the contribution of MMPs in eutrophic remodeling appears less crucial. Key Words: nitric oxide synthase Ⅲ arteries V ascular remodeling is considered an adaptive response to elevation of arterial pressure to normalize the wall tension. In essential hypertension, large artery remodeling is characterized by an increase in media thickness-lumen diameter (M/L) ratio and cross-sectional area (CSA). This augmentation of media mass, or hypertrophic remodeling, is explained by changes in size or number of vascular smooth muscle cells (VSMCs) and matrix collagen deposition. 1 In resistance arteries (diameter Ͻ300 m), essential hypertension is associated with a reduced lumen and increased M/L ratio but without CSA increase, producing a type of remodeling designated as inward eutrophic remodeling. 2 To explain this different response between large and small arteries, it is suggested that small arteries are not submitted to an augmented wall stress because they are initially constricted. 3-5 Thus, we hypothesized that inward eutrophic remodeling, which appears as a fixed form of vasoconstriction, could proceed through specific modifications of VSMC-matrix interactions.As in essential hypertension, chronic inhibition of NO synthesis with the L-arginine analogue N -nitro-L-arginine methyl ester (L-NAME) produces hypertrophic re...

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Section: Bouvet Et Al Matrix Changes During Eutrophic Remodelingmentioning

confidence: 56%

Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition

et al. 2005

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“…15,24,27,36,91 MMP-9 inhibitors have showed utility in protection from ICH. [92][93][94] Inhibiting MMP-9 may also negate the harmful effects of AVMrelated inflammatory responses. Lee et al 28,29 evaluated the effect of the MMP-9 inhibitors minocycline and pyrrolidine dithiocarbamate on an AVM mouse model and showed that MMP-9 blockade significantly reduced the extent of hemorrhage.…”

Section: Potential Therapeutic Targetsmentioning

confidence: 99%

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

Mouchtouris

Jabbour

Starke

et al. 2014

J Cereb Blood Flow Metab

128

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Cerebral arteriovenous malformations (AVMs) entail a significant risk of intracerebral hemorrhage owing to the direct shunting of arterial blood into the venous vasculature without the dissipation of the arterial blood pressure. The mechanisms involved in the growth, progression and rupture of AVMs are not clearly understood, but a number of studies point to inflammation as a major contributor to their pathogenesis. The upregulation of proinflammatory cytokines induces the overexpression of cell adhesion molecules in AVM endothelial cells, resulting in enhanced recruitment of leukocytes. The increased leukocyte-derived release of metalloproteinase-9 is known to damage AVM walls and lead to rupture. Inflammation is also involved in altering the AVM angioarchitecture via the upregulation of angiogenic factors that affect endothelial cell proliferation, migration and apoptosis. The effects of inflammation on AVM pathogenesis are potentiated by certain single-nucleotide polymorphisms in the genes of proinflammatory cytokines, increasing their protein levels in the AVM tissue. Furthermore, studies on metalloproteinase-9 inhibitors and on the involvement of Notch signaling in AVMs provide promising data for a potential basis for pharmacological treatment of AVMs. Potential therapeutic targets and areas requiring further investigation are highlighted.

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“…Balloon angioplasty was performed as previously described. 31 After balloon injury, an intra-arterial bolus of 200-g CRP was injected through the same entrance at left external artery by a silicon tube, detained for 1 minute, and followed by an injection of 1-mL low-temperature gelling agarose (Type VII, Sigma) mixed with CRP at a concentration of 100 g/mL around the carotid artery. 32 In a subgroup, losartan in the drinking water (15 mg/kg per day) was started 3 days before balloon angioplasty and continued to the end of experiment.…”

Section: Carotid Artery Balloon Angioplasty Modelmentioning

confidence: 99%

“…Rats were euthanized at various time points after injury, chosen as follows on the basis of previous studies elucidating the kinetics of the injury response. 31 Cross-sectional rings (4 mol/L) were cut at 5 mm before the bifurcation of internal and external carotid arteries and stained with hematoxylin and eosin, Trichromes stain, smooth muscle cell ␣-actin (DAKO), 5-bromo-2Ј-deoxyuridine (BrdU, DAKO), Picro-Sirius Red (for collagen staining, measured by confocal microscope), AT 1 -R, CD45, histone H1, and monocyte and macrophage. Smooth muscle cell proliferation was measured in the media and intima with 100 mg of BrdU injected intraperitoneally 24 hours before sacrifice.…”

Section: Carotid Artery Balloon Angioplasty Modelmentioning

confidence: 99%

C-Reactive Protein Upregulates Angiotensin Type 1 Receptors in Vascular Smooth Muscle

et al. 2003

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Background-Accumulating evidence suggests that C-reactive protein (CRP), in addition to predicting vascular disease, may actively facilitate lesion formation by inciting endothelial cell activation. Given the central importance of angiotensin type 1 receptor (AT 1 -R) in the pathogenesis of atherosclerosis, we examined the effects of CRP on AT 1 -R expression and kinetics in vascular smooth muscle (VSM) cells. In addition, the effects of CRP on VSM migration, proliferation, and reactive oxygen species (ROS) production were evaluated in the presence and absence of the angiotensin receptor blocker, losartan. Lastly, the effects of CRP (and losartan) on neointimal formation were examined in vivo in a rat carotid angioplasty model. Methods and Results-The effects of human recombinant CRP (0 to 100 g/mL) on AT 1 -R transcript, mRNA stability, and protein expression were studied in cultured human VSM cells. AT 1 -R binding was assessed with 125 I-labeled angiotensin II (Ang II). VSM migration was assessed with wound cell migration assays, whereas VSM proliferation was determined with [3 H]-incorporation and cell number. The effects of CRP (and losartan) on Ang II-induced ROS production were evaluated by 2Ј,7Ј-dichlorofluorescein fluorescence. Lastly, the effects of CRP (and losartan) on neointimal formation, VSM cell migration, proliferation, and matrix formation were studied in vivo in a rat carotid artery balloon injury model. CRP markedly upregulated AT 1 -R mRNA and protein expression and increased AT 1 -R number on VSM cells. CRP promoted VSM migration and proliferation in vitro and increased ROS production. Furthermore, CRP potentiated the effects of Ang II on these processes. In the rat carotid artery angioplasty model, exposure to CRP resulted in an increase in cell migration and proliferation, collagen and elastin content, and AT 1 -R expression, as well as an increase in neointimal formation; these effects were attenuated by losartan. Conclusions-CRP, at concentrations known to predict cardiovascular events, upregulates AT 1 -R-mediated atherosclerotic events in vascular smooth muscle in vitro and in vivo. These data lend credence to the notion that CRP functions as a proatherosclerotic factor as well as a powerful risk marker.

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Doxycycline Modulates Smooth Muscle Cell Growth, Migration, and Matrix Remodeling after Arterial Injury

Cited by 183 publications

References 42 publications

Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition

Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

C-Reactive Protein Upregulates Angiotensin Type 1 Receptors in Vascular Smooth Muscle

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