Abstract P086: Endothelial Cullin3 Mutation Causes Vascular Dysfunction, Arterial Stiffening, And Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Jing Wu ◽  
Shi Fang ◽  
Sebastiao Donato Silva ◽  
Chunyan Hu ◽  
Adokole J Otanwa ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Phosphatase ◽  
Low Frequency ◽  
Power Spectral Analysis ◽  
No Production ◽  
Night Time ◽  
Arterial Stiffening ◽  
Enos Activity ◽  
Primary Mouse

Mutations in CULLIN3 gene (causing in-frame deletion of exon 9, termed Cul3Δ9) cause human hypertension (HT), which is driven by a combination of renal tubular and vascular mechanisms. We have previously shown that disruption of Cullin3 (CUL3) in vascular smooth muscle impairs nitric oxide (NO) signaling and vasodilation through decreased cGMP bioavailability, strongly supporting a role of vascular CUL3 in blood pressure (BP) regulation. To test the importance of endothelial Cul3 in vivo , we bred the conditionally activatable Cul3Δ9 mice with tamoxifen-inducible Tie2-CRE ERT2 mice. Four weeks after tamoxifen, the resultant mice (E-Cul3Δ9) developed nocturnal HT (Night time peak systolic BP, E-Cul3Δ9: 135±3 vs Control: 124±3 mmHg) and arterial stiffening (pulse wave velocity, 3.7±0.3 vs 2.7±0.1 m/s). No difference was seen in daytime BP. To determine whether vascular remodeling impairs baroreflex function, we performed power spectral analysis. Heart rate (HR), low frequency/high frequency ratio of HR variability, and baroreflex gain were comparable between control and E-Cul3Δ9 mice, suggesting there was no change in cardiac sympathetic nerve activity. However, low frequency amplitude of arterial pressure variability (16±4 vs 7±2 mmHg 2 ) at night was markedly augmented in E-Cul3Δ9 mice, suggesting increased sympathetic activity in vascular tone regulation. Consistently, E-Cul3Δ9 mice exhibited impaired endothelial-dependent relaxation in carotid artery (Max ACh relaxation: 69% vs 84%) and cerebral resistance basilar artery (41% vs 77%). No difference in smooth muscle function was observed. Expression of Cul3Δ9 in primary mouse aortic endothelial cells markedly decreased wild type Cul3 protein, phosphorylated eNOS, and NO production. Because protein phosphatase 2A (PP2A) is a known Cul3 substrate which dephosphorylates eNOS, we determined whether impaired eNOS activity was attributable to PP2A. Cul3Δ9-induced impairment of eNOS activity was rescued by a selective PP2A inhibitor Okadaic Acid (4 nM), but not by a Protein Phosphatase 1 inhibitor Tautomycetin (4 nM). Thus, CUL3 mutations in the endothelium contribute to human HT in part through decreased NO bioavailability, endothelial dysfunction and secondary sympathoexcitation.

Abstract MP14: Endothelial Cullin3 Mutation Causes Decreased Nitric Oxide (NO) Bioavailability And Vascular Dysfunction Through Protein Phosphatase 2A

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Jing Wu ◽  
Shi Fang ◽  
Chunyan Hu ◽  
Adokole Otanwa ◽  
Daniel Brozoski ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Low Frequency ◽  
No Production ◽  
Specific Expression ◽  
Arterial Stiffening ◽  
Enos Activity ◽  
Nighttime Blood Pressure ◽  
Primary Mouse ◽  
No Bioavailability

Mutations in CULLIN3 gene (in-frame deletion of exon 9, termed Cul3Δ9) cause human hypertension (HT) driven by a combination of renal tubular and vascular mechanisms. To test the importance of endothelial Cul3 in vivo , we bred the conditionally activatable Cul3Δ9 mice with tamoxifen-inducible Tie2-CRE ERT2 mice. The resultant mice (E-Cul3Δ9) developed arterial stiffening (pulse wave velocity, 3.7±0.3 vs 2.7±0.1 m/s, n=5-7, p<0.05) and a trend towards elevated nighttime blood pressure (peak systolic BP, E-Cul3Δ9 136±3 vs control 128±3 mmHg, n=9-11) that were not associated with any alterations in locomotion, food/water intake or sleep/wake behaviors. No difference was seen in daytime BP. To determine whether vascular remodeling impairs baroreflex function, we performed power spectral analysis. Heart rate (HR), low frequency/high frequency ratio of HR variability, and baroreflex gain were comparable between control and E-Cul3Δ9 mice, suggesting no change in cardiac sympathetic nerve activity. However, low frequency amplitude of arterial pressure variability (16±4 vs 7±2 mmHg 2 , n=5-9, p<0.05) at night was markedly augmented in E-Cul3Δ9 mice, suggesting increased sympathetic activity in vascular tone regulation. Consistently, E-Cul3Δ9 mice exhibited impaired endothelial-dependent relaxation in carotid artery (max ACh relaxation: 69% vs 84%, n=5-7, p<0.05) and cerebral resistance basilar artery (41% vs 77%, n=4-6, p<0.05). However, no dilatory impairment in mesenteric resistance artery and no difference in smooth muscle function were observed, suggesting that the effects of Cul3Δ9 are arterial bed specific. Expression of Cul3Δ9 in primary mouse aortic endothelial cells markedly decreased wild type Cul3 protein, phosphorylated eNOS and NO production. Protein phosphatase (PP) 2A, a known Cul3 substrate, dephosphorylates eNOS. Therefore, we determined whether impaired eNOS activity was attributable to PP2A. Cul3Δ9-induced impairment of eNOS activity was rescued by a selective PP2A inhibitor okadaic acid (4nM), but not by a PP1 inhibitor tautomycetin (4nM). Thus, CUL3 mutations in the endothelium may contribute to human HT in part through decreased endothelial NO bioavailability, arterial stiffening and secondary sympathoexcitation.

scholarly journals A theoretical model of nitric oxide transport in arterioles: frequency- vs. amplitude-dependent control of cGMP formation

2004 ◽  
Vol 286 (3) ◽  
pp. H1043-H1056 ◽  
Author(s):  
Nikolaos M. Tsoukias ◽  
Mahendra Kavdia ◽  
Aleksander S. Popel
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Muscle Tone ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
No Production ◽  
Cgmp Formation

Nitric oxide (NO) plays many important physiological roles, including the regulation of vascular smooth muscle tone. In response to hemodynamic or agonist stimuli, endothelial cells produce NO, which can diffuse to smooth muscle where it activates soluble guanylate cyclase (sGC), leading to cGMP formation and smooth muscle relaxation. The close proximity of red blood cells suggests, however, that a significant amount of NO released will be scavenged by blood, and thus the issue of bioavailability of endothelium-derived NO to smooth muscle has been investigated experimentally and theoretically. We formulated a mathematical model for NO transport in an arteriole to test the hypothesis that transient, burst-like NO production can facilitate efficient NO delivery to smooth muscle and reduce NO scavenging by blood. The model simulations predict that 1) the endothelium can maintain a physiologically significant amount of NO in smooth muscle despite the presence of NO scavengers such as hemoglobin and myoglobin; 2) under certain conditions, transient NO release presents a more efficient way for activating sGC and it can increase cGMP formation severalfold; and 3) frequency-rather than amplitude-dependent control of cGMP formation is possible. This suggests that it is the frequency of NO bursts and perhaps the frequency of Ca2+ oscillations in endothelial cells that may limit cGMP formation and regulate vascular tone. The proposed hypothesis suggests a new functional role for Ca2+ oscillations in endothelial cells. Further experimentation is needed to test whether and under what conditions in silico predictions occur in vivo.

Short-term exposure to homocysteine depresses rat aortic contractility by an endothelium-dependent mechanism

2000 ◽  
Vol 78 (6) ◽  
pp. 500-506 ◽  
Author(s):  
S Wang ◽  
G Wright ◽  
J Harrah ◽  
R Touchon ◽  
W McCumbee ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Nitric Oxide Synthase ◽  
Contractile Response ◽  
Fold Increase ◽  
No Production ◽  
Short Term ◽  
Short Term Exposure ◽  
Oxide Synthase

The effect of short-term exposure to homocysteine (Hcy) on the contractile characteristics of rat aortic tissue was assessed both in vitro and in vivo. The contractile response of Hcy-treated aortic rings in culture for 1 or 4 days was unchanged from control responses. By comparison, aortic rings from animals injected with Hcy showed marked attenuation of response compared with controls injected with saline, cysteine or methionine. The contractile response to K+ was decreased within 24 hours of Hcy injection, whereas the response to both K+ (-27%) and noradrenaline (-56%) was significantly decreased by 4 days. In contrast, the contractile response to phorbol-12,13-dibutyrate was not different between Hcy and control groups. Intimal rubbing completely restored the responsiveness of Hcy-treated tissue to K+ and noradrenaline. By comparison, L-NAME only partially restored contractile responsiveness, while the cyclooxygenase inhibitor indomethacin had no effect on contractile attenuation induced by Hcy. Western blot analysis showed a 2-fold increase of endothelial nitric oxide synthase (eNOS) and a 3-fold increase in inducible nitric oxide synthase (iNOS) protein expression in the aortic endothelial cells from Hcy-injected rats. The results indicate an early detectable effect of Hcy on the in vivo contractile properties of vascular smooth muscle. The effect is endothelium-mediated and may vary depending on the agonist studied. The mechanism is uncertain but appears to involve increased nitric oxide (NO) production. Finally, the data suggest that attenuation of contraction may not be due to a direct effect of Hcy but that the compound is modified or acts indirectly in vivo.Key words: nitric oxide, nitric oxide synthase, in vivo, smooth muscle.

Vascular reactivity and endothelial NOS activity in rat thoracic aorta during and after hyperbaric oxygen exposure

2006 ◽  
Vol 291 (4) ◽  
pp. H1988-H1998 ◽  
Author(s):  
Jonas Hink ◽  
Stephen R. Thom ◽  
Ulf Simonsen ◽  
Inger Rubin ◽  
Erik Jansen
Keyword(s):  
Catalytic Activity ◽  
Polyethylene Glycol ◽  
Hyperbaric Oxygen ◽  
Vascular Reactivity ◽  
Superoxide Production ◽  
No Production ◽  
Enos Activity ◽  
No Bioavailability

Accumulating evidence suggests that hyperbaric oxygen (HBO) stimulates neuronal nitric oxide (NO) synthase (NOS) activity, but the influence on endothelial NOS (eNOS) activity and vascular NO bioavailability remains unclear. We used a bioassay employing rat aortic rings to evaluate vascular NO bioavailability. HBO exposure to 2.8 atm absolute (ATA) in vitro decreased ACh relaxation. This effect remained unchanged, despite treatment with SOD-polyethylene glycol and catalase-polyethylene glycol, suggesting that the reduction in endothelium-derived NO bioavailability was independent of superoxide production. In vitro HBO induced contraction of resting aortic rings with and without endothelium, and these contractions were reduced by the NOS inhibitor Nω-nitro-l-arginine. In addition, in vitro HBO attenuated the vascular contraction produced by norepinephrine, and this effect was reversed by Nω-nitro-l-arginine, but not by endothelial denudation. These findings indicate stimulation of extraendothelial NO production during HBO exposure. A radiochemical assay was used to assess NOS activity in rat aortic endothelial cells. Catalytic activity of eNOS in cell homogenates was not decreased by HBO, and in vivo HBO exposure to 2.8 ATA was without effect on eNOS activity and/or vascular NO bioavailability in vitro. We conclude that HBO reduces endothelium-derived NO bioavailability independent of superoxide production, and this effect seems to be unrelated to a decrease in eNOS catalytic activity. In addition, HBO increases the resting tone of rat aortic rings and attenuates the contractile response to norepinephrine by endothelium-independent mechanisms that involve extraendothelial NO production.

scholarly journals Venular endothelium-derived NO can affect paired arteriole: a computational model

2006 ◽  
Vol 290 (2) ◽  
pp. H716-H723 ◽  
Author(s):  
Mahendra Kavdia ◽  
Aleksander S. Popel
Keyword(s):  
Smooth Muscle ◽  
Computational Model ◽  
Reaction Rate ◽  
Soluble Guanylate Cyclase ◽  
Experimental Studies ◽  
Vascular Wall ◽  
No Production ◽  
Wide Range ◽  
Venular Endothelium

Venular endothelial cells can release nitric oxide (NO) in response to intraluminal flow both in isolated venules and in vivo. Experimental studies suggest that venular endothelium-released NO causes dilation of the adjacent paired arteriole. In the vascular wall, NO stimulates its target hemoprotein, soluble guanylate cyclase (sGC), which relaxes smooth muscle cells. In this study, a computational model of NO transport for an arteriole and venule pair was developed to determine the importance of the venular endothelium-released NO and its transport to the adjacent arteriole in the tissue. The model predicts that the tissue NO levels are affected within a wide range of parameters, including NO-red blood cell reaction rate and NO production rate in the arteriole and venule. The results predict that changes in the venular NO production affected not only venular endothelial and smooth muscle NO concentration but also endothelial and smooth muscle NO concentration in the adjacent arteriole. This suggests that the anatomy of microvascular tissue can permit the transport of NO from arteriolar to venular side, and vice versa, and may provide a mechanism for dilation of proximal arterioles by venules. These results will have significant implications for our understanding of tissue NO levels in both physiological and pathophysiological conditions.

Effective diffusion distance of nitric oxide in the microcirculation

1998 ◽  
Vol 274 (5) ◽  
pp. H1705-H1714 ◽  
Author(s):  
Mark W. Vaughn ◽  
Lih Kuo ◽  
James C. Liao
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Guanylyl Cyclase ◽  
Effective Diffusion ◽  
Regulatory Function ◽  
Systemic Hypertension ◽  
No Production ◽  
Diffusion Distance ◽  
Degradation Rates

Despite its well-documented importance, the mechanism for nitric oxide (NO) transport in vivo is still unclear. In particular, the effect of hemoglobin-NO interaction and the range of NO action have not been characterized in the microcirculation, where blood flow is optimally regulated. Using a mathematical model and experimental data on NO production and degradation rates, we investigated factors that determine the effective diffusion distance of NO in the microcirculation. This distance is defined as the distance within which NO concentration is greater than the equilibrium dissociation constant (0.25 μM) of soluble guanylyl cyclase, the target enzyme for NO action. We found that the size of the vessel is an important factor in determining the effective diffusion distance of NO. In ∼30- to 100-μm-ID microvessels the luminal NO concentrations and the abluminal effective diffusion distance are maximal. Furthermore, the model suggests that if the NO-erythrocyte reaction rate is as fast as the rate reported for the in vitro NO-hemoglobin reaction, the NO concentration in the vascular smooth muscle will be insufficient to stimulate smooth muscle guanylyl cyclase effectively. In addition, the existence of an erythrocyte-free layer near the vascular wall is important in determining the effective NO diffusion distance. These results suggest that 1) the range of NO action may exhibit significant spatial heterogeneity in vivo, depending on the size of the vessel and the local chemistry of NO degradation, 2) the NO binding/reaction constant with hemoglobin in the red blood cell may be much smaller than that with free hemoglobin, and 3) the microcirculation is the optimal site for NO to exert its regulatory function. Because NO exhibits vasodilatory function and antiatherogenic activity, the high NO concentration and its long effective range in the microcirculation may serve as intrinsic factors to prevent the development of systemic hypertension and atherosclerotic pathology in microvessels.

scholarly journals Smooth-muscle caldesmon phosphatase is SMP-I, a type 2A protein phosphatase

1993 ◽  
Vol 293 (1) ◽  
pp. 35-41 ◽  
Author(s):  
M D Pato ◽  
C Sutherland ◽  
S J Winder ◽  
M P Walsh
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Gel Filtration ◽  
Cytosolic Fraction ◽  
Chicken Gizzard ◽  
Kinase C

Caldesmon phosphatase was identified in chicken gizzard smooth muscle by using as substrates caldesmon phosphorylated at different sites by protein kinase C, Ca2+/calmodulin-dependent protein kinase II and cdc2 kinase. Most (approximately 90%) of the phosphatase activity was recovered in the cytosolic fraction. Gel filtration after (NH4)2SO4 fractionation of the cytosolic fraction revealed a single major peak of phosphatase activity which coeluted with calponin phosphatase [Winder, Pato and Walsh (1992) Biochem. J. 286, 197-203] and myosin LC20 phosphatase. Further purification of caldesmon phosphatase was achieved by sequential chromatography on columns of DEAE-Sephacel, omega-amino-octyl-agarose, aminopropyl-agarose and thiophosphorylated myosin LC20-Sepharose. A single peak of caldesmon phosphatase activity was detected at each step of the purification. The purified phosphatase was identified as SMP-I [Pato and Adelstein (1980) J. Biol. Chem. 255, 6535-6538] by subunit composition (three subunits, of 60, 55 and 38 kDa) and Western blotting using antibodies against the holoenzyme which recognize all three subunits and antibodies specific for the 38 kDa catalytic subunit. SMP-I is a type 2A protein phosphatase [Pato, Adelstein, Crouch, Safer, Ingebritsen and Cohen (1983) Eur. J. Biochem. 132, 283-287; Winder et al. (1992), cited above]. Consistent with the conclusion that SMP-I is the major caldesmon phosphatase of smooth muscle, purified SMP-I from turkey gizzard dephosphorylated all three phosphorylated forms of caldesmon, whereas SMP-II, -III and -IV were relatively ineffective. Kinetic analysis of dephosphorylation by chicken gizzard SMP-I of the three phosphorylated caldesmon species and calponin phosphorylated by protein kinase C indicates that calponin is a significantly better substrate of SMP-I than are any of the three phosphorylated forms of caldesmon. We therefore suggest that caldesmon phosphorylation in vivo can be maintained after kinase inactivation due to slow dephosphorylation by SMP-I, whereas calponin and myosin are rapidly dephosphorylated by SMP-I and SMP-III/SMP-IV respectively. This may have important functional consequences in terms of the contractile properties of smooth muscle.

Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10

2005 ◽  
Vol 288 (5) ◽  
pp. L868-L873 ◽  
Author(s):  
Bill T. Ameredes ◽  
Jigme M. Sethi ◽  
He-Liang Liu ◽  
Augustine M. K. Choi ◽  
William J. Calhoun
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Tracheal Ring ◽  
No Production ◽  
Muscle Contractility ◽  
Smooth Muscle Contractility ◽  
Nos Inhibitors

Interleukin (IL)-10 is an anti-inflammatory cytokine implicated in the regulation of airway inflammation in asthma. Among other activities, IL-10 suppresses production of nitric oxide (NO); consequently, its absence may permit increased NO production, which can affect airway smooth muscle contractility. Therefore, we investigated airway reactivity (AR) in response to methacholine (MCh) in IL-10 knockout (−/−) mice compared with wild-type C57BL/6 (C57) mice, in which airway NO production was measured as exhaled NO (ENO), and NO production was altered with administration of either NO synthase (NOS)-specific inhibitors or recombinant murine (rm)IL-10. AR, measured as enhanced pause in vivo, and tracheal ring tension in vitro were lower in IL-10−/− mice by 25–50%, which was associated with elevated ENO levels (13 vs. 7 ppb). Administration of NOS inhibitors NG-nitro-l-arginine methyl ester (8 mg/kg ip) or l- N6-(1-iminoethyl)-lysine (3 mg/kg ip) to IL-10−/− mice decreased ENO by an average of 50%, which was associated with increased AR, to levels similar to C57 mice. ENO in IL-10−/− mice decreased in a dose-dependent fashion in response to administered rmIL-10, to levels similar to C57 mice (7 ppb), which was associated with a 30% increment in AR. Thus increased NO production in the absence of IL-10, decreased AR, which was reversed with inhibition of NO, either by inhibition of NOS, or with reconstitution of IL-10. These findings suggest that airway NO production can modulate airway smooth muscle contractility, resulting in airway hyporesponsiveness when IL-10 is absent.

scholarly journals Protective Effects of Low-Frequency Magnetic Fields on Cardiomyocytes from Ischemia Reperfusion InjuryviaROS and NO/ONOO−

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Sai Ma ◽  
Zhengxun Zhang ◽  
Fu Yi ◽  
Yabin Wang ◽  
Xiaotian Zhang ◽  
...  
Keyword(s):  
Magnetic Fields ◽  
Cell Viability ◽  
Ischemia Reperfusion ◽  
Low Frequency ◽  
Neonatal Rat ◽  
Ros Generation ◽  
No Production ◽  
Protective Effects ◽  
Rat Cardiomyocytes

Background. Cardiac ischemia reperfusion (I/R) injury is associated with overproduction of reactive oxygen species (ROS). Low frequency pulse magnetic fields (LFMFs) have been reported to decrease ROS generation in endothelial cells. Whether LFMFs could assert protective effects on myocardial from I/R injuryviaROS regulation remains unclear.Methods. To simulatein vivocardiac I/R injury, neonatal rat cardiomyocytes were subjected to hypoxia reoxygenation (H/R) with or without exposure to LFMFs. Cell viability, apoptosis index, ROS generation (includingO2-and ONOO−), and NO production were measured in control, H/R, and H/R + LFMF groups, respectively.Results. H/R injury resulted in cardiomyocytes apoptosis and decreased cell viability, whereas exposure to LFMFs before or after H/R injury significantly inhibited apoptosis and improved cell viability (P<0.05). LFMFs treatment could suppress ROS (includingO2-and ONOO−) generation induced by H/R injury, combined with decreased NADPH oxidase activity. In addition, LFMFs elevated NO production and enhanced NO/ONOO−balance in cardiomyocytes, and this protective effect wasviathe phosphorylation of endothelial nitric oxide synthase (eNOS).Conclusion. LFMFs could protect myocardium against I/R injuryviaregulating ROS generation and NO/ONOO−balance. LFMFs treatment might serve as a promising strategy for cardiac I/R injury.

Abstract 348: TNFα-induced Expression of Adamts7 Affects Primary Mouse Smooth Muscle Cell Migration ex vivo

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Robert C Bauer ◽  
Xuan Zhang ◽  
Junichiro Tohyama ◽  
Jian Cui ◽  
Mikhaila A Smith ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Ex Vivo ◽  
Fold Increase ◽  
Western Diet ◽  
Small Data ◽  
Data Sets ◽  
Genomic Locus ◽  
Public And Private ◽  
Primary Mouse

ADAMTS7 has recently been identified as a novel genomic locus associated with coronary artery disease (CAD) in humans. We have recently shown that deficiency of Adamts7 in hyperlipidemic mouse models reduces atherosclerosis following prolonged western diet feeding, however the mechanism of this reduction remains unknown. Using a β-galactosidase (β-gal) reporter, we observed that vascular Adamts7 expression is induced in response to both mechanical injury and western diet feeding in a transient manner, and this expression predominantly colocalizes to vascular smooth muscle cells (VSMCs). We investigated the ability of multiple cytokines and growth factors (PDGF-BB, TNFα, IFNγ, and Angiotensin II) to stimulate Adamts7 expression in primary mouse VSMCs, and found that of these only TNFα induced Adamts7 expression (5.5-fold, p=0.0007). We determined the expression of Adamts7 and TNFα in whole aortas and aortic roots of Apoe-/- mice at various timepoints of western diet feeding, and found trends towards increased Adamts7 expression while TNFα expression consistently increased over the course of the experiment (4.4-fold increase, p=0.002). We next examined proliferation and migration of primary VSMCs from Adamts7 WT and KO animals. Unstimulated Adamts7 KO VSMCs had no observable difference in migration as compared to WT controls. However, in the setting of TNFα stimulation we observed a decrease in migration of Adamts7 KO VSMCs plated on collagen I (50% reduction, p=0.02) and laminin (60% reduction, p=0.0002). Finally, using both public and private data sets, we assessed if associations exist between SNPs in and around the human ADAMTS7 locus and the expression of ADAMTS7 in relevant tissues. In small data sets we find that SNPs with genome-wide association with CAD also associate with ADAMTS7 expression, and the direction of this association is consistent with our in vivo reduction of atherosclerosis in Adamts7 KO animals. In summary, Adamts7 expression in mice is induced in response to vascular injury, perhaps mediated by TNFα expression, and this induction can modulate VSMC migration. These observations present a novel mechanistic paradigm for ADAMTS7 modulation of atherogenesis and suggest its inhibition might reduce CHD in clinic.

Sign in / Sign up

Export Citation Format

Share Document