Vascular Section

Dartmouth, Lebanon

Vascular Section

Dartmouth, Lebanon
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Mulligan-Kehoe M.J.,Vascular Section | Fiering S.N.,Immunology and Microbiology and Pathology | Hickey W.F.,University of Southern New Hampshire
Journal of Biological Chemistry | Year: 2016

Acyl-CoA:cholesterol acyltransferase 1 (Acat1) converts cellular cholesterol to cholesteryl esters and is considered a drug target for treating atherosclerosis. However, in mouse models for atherosclerosis, global Acat1 knockout (Acat1) did not prevent lesion development. Acat1 increased apoptosis within lesions and led to several additional undesirable phenotypes, including hair loss, dry eye, leukocytosis, xanthomatosis, and a reduced life span. To determine the roles of Acat1 in monocytes/macrophages in atherosclerosis, we produced a myeloid-specific Acat1 knockout (Acat1M/M) mouse and showed that, in the Apoe knockout (Apoe) mouse model for atherosclerosis, Acat1M/M decreased the plaque area and reduced lesion size without causing leukocytosis, dry eye, hair loss, or a reduced life span. Acat1M/Menhanced xanthomatosis in apoe mice, a skin disease that is not associated with diet-induced atherosclerosis in humans. Analyses of atherosclerotic lesions showed that Acat1M/M reduced macrophage numbers and diminished the cholesterol and cholesteryl ester load without causing detectable apoptotic cell death. Leukocyte migration analysis in vivo showed that Acat1M/M caused much fewer leukocytes to appear at the activated endothelium. Studies in inflammatory (Ly6Chi-positive) monocytes and in cultured macrophages showed that inhibiting ACAT1 by gene knockout or by pharmacological inhibition caused a significant decrease in integrin β 1 (CD29) expression in activated monocytes/macrophages. The sparse presence of lesion macrophages without Acat1 can therefore, in part, be attributed to decreased interaction between inflammatory monocytes/macrophages lacking Acat1 and the activated endothelium. We conclude that targeting ACAT1 in a myeloid cell lineage suppresses atherosclerosis progression while avoiding many of the undesirable side effects caused by global Acat1 inhibition. ©2016 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | Pathology, Vascular Section. and Immunology and Microbiology and.
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2016

Acyl-CoA:cholesterol acyltransferase 1 (Acat1) converts cellular cholesterol to cholesteryl esters and is considered a drug target for treating atherosclerosis. However, in mouse models for atherosclerosis, global Acat1 knockout (Acat1(-/-)) did not prevent lesion development. Acat1(-/-) increased apoptosis within lesions and led to several additional undesirable phenotypes, including hair loss, dry eye, leukocytosis, xanthomatosis, and a reduced life span. To determine the roles of Acat1 in monocytes/macrophages in atherosclerosis, we produced a myeloid-specific Acat1 knockout (Acat1(-M/-M)) mouse and showed that, in the Apoe knockout (Apoe(-/-)) mouse model for atherosclerosis, Acat1(-M/-M) decreased the plaque area and reduced lesion size without causing leukocytosis, dry eye, hair loss, or a reduced life span. Acat1(-M/-M) enhanced xanthomatosis in apoe(-/-) mice, a skin disease that is not associated with diet-induced atherosclerosis in humans. Analyses of atherosclerotic lesions showed that Acat1(-M/-M) reduced macrophage numbers and diminished the cholesterol and cholesteryl ester load without causing detectable apoptotic cell death. Leukocyte migration analysis in vivo showed that Acat1(-M/-M) caused much fewer leukocytes to appear at the activated endothelium. Studies in inflammatory (Ly6C(hi)-positive) monocytes and in cultured macrophages showed that inhibiting ACAT1 by gene knockout or by pharmacological inhibition caused a significant decrease in integrin 1 (CD29) expression in activated monocytes/macrophages. The sparse presence of lesion macrophages without Acat1 can therefore, in part, be attributed to decreased interaction between inflammatory monocytes/macrophages lacking Acat1 and the activated endothelium. We conclude that targeting ACAT1 in a myeloid cell lineage suppresses atherosclerosis progression while avoiding many of the undesirable side effects caused by global Acat1 inhibition.


Mollmark J.,Vascular Section | Mollmark J.,Vascular Research Center | Ravi S.,Vascular Research Center | Sun B.,Vascular Section | And 7 more authors.
Circulation Research | Year: 2011

Rationale: The antiangiogenic activity of rPAI-123, a truncated plasminogen activator inhibitor-1 (PAI-1) protein, induces vasa vasorum collapse and significantly reduces plaque area and plaque cholesterol in hypercholesterolemic low-density lipoprotein receptor-deficient/apolipoprotein B48-deficient mice. Objective: The objective of this study was to examine rPAI-123-stimulated mechanisms that cause vasa vasorum collapse. Methods and results: The rPAI-123 protein opposed PAI-1 antiproteolytic function by stimulating a 1.6-fold increase in plasmin activity compared with the saline-treated counterpart. The increased proteolytic activity corresponded to increased activity of matrix metalloproteinase-3 and degradation of fibrin(ogen), nidogen, and perlecan in the adventitia of descending aortas. PAI-1 activity was reduced by 48% in response to rPAI-123; however, PAI-1 protein expression levels were similar in the rPAI-123- and saline-treated hypercholesterolemic mice. Coimmunoprecipitation assays demonstrated a novel PAI-1-plasminogen complex in protein from the descending aorta of rPAI-1 23- and saline-treated mice, but complexed PAI-1 was 1.6-fold greater in rPAI-123-treated mice. Biochemical analyses demonstrated that rPAI-123 and PAI-1 binding interactions with plasminogen increased plasmin activity and reduced PAI-1 antiproteolytic activity. Conclusions: We conclude that rPAI-123 causes regression or collapse of adventitial vasa vasorum in hypercholesterolemic mice by stimulating an increase in plasmin activity. The rPAI-123-enhanced plasmin activity was achieved through a novel mechanism by which rPAI-123 and PAI-1 bound plasminogen in a cooperative manner to increase plasmin activity and reduce PAI-1 activity. © 2011 American Heart Association, Inc.


Mulligan-Kehoe M.J.,Vascular Section
Trends in Cardiovascular Medicine | Year: 2013

The vasa vasorum are unique networks of vessels that become angiogenic in response to changes in the vessel wall. Structural studies, using various imaging modalities, show that the vasa vasorum form a plexus of microvessels during the atherosclerotic disease process. The events that stimulate vasa vasorum neovascularization remain unclear. Anti-angiogenic molecules have been shown to inhibit/regress the neovascularization; they provide significant insight into vasa vasorum function, structure, and specific requirements for growth and stability. This review discusses evidence for and against potential stimulators of vasa vasorum neovascularization. Anti-angiogenic rPAI-123, a truncated isoform of plasminogen activator inhibitor-1 (PAI-1) stimulates a novel pathway for regulating plasmin activity. This mechanism contributes significantly to vasa vasorum regression/collapse and is discussed as a model of regression. © 2013 Elsevier Inc.


Baeyens N.,Yale University | Mulligan-Kehoe M.J.,Vascular Section | Corti F.,Yale University | Simon D.D.,Yale University | And 7 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4-/-) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4-/- mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression of S4. This effect was highly specific, as flow activation of VEGF receptor 2 and NF-κB was normal. S4-depleted ECs aligned in cyclic stretch and even elongated under flow, although nondirectionally. EC alignment was previously found to have a causal role in modulating activation of inflammatory versus antiinflammatory pathways by flow. Consistent with these results, S4-depleted HUVECs in long-term laminar flow showed increased activation of proinflammatory NF-κB and decreased induction of antiinflammatory kruppel-like factor (KLF) 2 and KLF4. Thus, S4 plays a critical role in sensing flow direction to promote cell alignment and inhibit atherosclerosis.


PubMed | Yale University and Vascular Section
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4(-/-)) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4(-/-) mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression of S4. This effect was highly specific, as flow activation of VEGF receptor 2 and NF-B was normal. S4-depleted ECs aligned in cyclic stretch and even elongated under flow, although nondirectionally. EC alignment was previously found to have a causal role in modulating activation of inflammatory versus antiinflammatory pathways by flow. Consistent with these results, S4-depleted HUVECs in long-term laminar flow showed increased activation of proinflammatory NF-B and decreased induction of antiinflammatory kruppel-like factor (KLF) 2 and KLF4. Thus, S4 plays a critical role in sensing flow direction to promote cell alignment and inhibit atherosclerosis.

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