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Biomedical subjects

Peter L Weissberg

Publications and source records attributed to Peter L Weissberg.

At least 19 recordsLinked to original sources
PubMed2006

Antagonism of platelet-derived growth factor by perivascular gene transfer attenuates adventitial cell migration after vascular injury: new tricks for old dogs?

Migration of adventitial fibroblasts contributes to vascular remodeling after angioplasty. This study has used perivascular gene transfer of a truncated platelet-derived growth factor PDGF receptor (PDGFXR) to investigate whether antagonism of PDGF signaling alters adventitial cell migration after balloon injury in rat carotid arteries. Adenoviruses coordinating expression of beta-galactosidase (LacZ) and PDGFXR or LacZ and green fluorescent protein (GFP) were applied to the perivascular surface of arteries and balloon injury performed 4 days later. Vessels were excised at 3, 7, and 14 days to determine morphology and gene expression. Uninjured arteries only expressed LacZ positive cells in the adventitial compartment; however, after injury in LacZ and GFP transfected arteries, LacZ positive cells contributed to the population of cells within the media and neointima at 7-14 days. Overexpression of PDGFXR and LacZ resulted in a significant reduction in the number of LacZ labeled cells in the neointima after vascular injury, concomitant with reduced remodeling, collagen content, expression of matrix metalloproteinase-2, and increased levels of tissue inhibitors of metalloproteinase-1 and -2. We provide evidence that perivascular antagonism of PDGF attenuates remodeling and contribution of adventitial fibroblasts to neointima formation after balloon angioplasty. Perivascular gene transfer may represent a therapeutic strategy to reduce the incidence of restenosis.

Angioplasty, Balloon↗
PubMed2006

Radionuclide imaging for the detection of inflammation in vulnerable plaques.

Imaging of atheromatous plaques has traditionally centered on assessing the degree of luminal stenosis. More recently it has become clear that the vulnerable atherosclerotic plaques responsible for the majority of life-threatening syndromes are characterized by high numbers of inflammatory cells and proteins. This has highlighted the urgent need for suitable imaging techniques that can identify and quantify levels of inflammation within atheromatous lesions. Positron emission tomography and single-photon emission computed tomography imaging hold promise in this regard. Tracer compounds capable of assessing macrophage recruitment, foam cell generation, matrix metalloproteinase production, macrophage apoptosis, and macrophage metabolism have been developed and tested in the carotid and peripheral circulation. The identification of inflamed lesions within the coronary circulation, however, remains elusive owing to small plaque size, cardiac and respiratory motion, and lack of a suitable specific nuclear tracer.

Animals↗
PubMed2006

Imaging endothelin ET(B) receptors using [18F]-BQ3020: in vitro characterization and positron emission tomography (microPET).

The endothelin (ET) receptor system has been shown to play a role in a number of vascular diseases. We have synthesized 18F-and 11C-labeled radioligands to enable in vivo imaging of the fundamental processes involved in ET receptor pharmacology in normal and diseased tissue using positron emission tomography (PET). One aim is to elucidate the proposed role of the ET(B) subtype as clearing receptor, removing ET-1 from the circulation, and whether this is an important mechanism to limit the detrimental effects caused by upregulated ET-1 in disease. To image ET(B) receptors we have labeled the selective agonist BQ3020 with 18F. In vitro characterization verified that [18F]-BQ3020 bound with a single subnanomolar affinity (K(D) = 0.34 +/- 0.10 nM, B(max) = 9.23 +/- 3.70 fmol/mg protein) to human left ventricle. Binding of [18F]-BQ3020 to human kidney was inhibited by ET-1 and unlabeled BQ3020 but not by the ET(A) selective antagonist FR139317, confirming that selectivity for the ET(B) receptor was retained. In vitro autoradiography revealed, as expected, high levels of ET(B) receptor densities in lung and kidney medulla, whereas kidney cortex and heart showed lower levels of ET(B) receptor densities. Furthermore, a high level of [18F]-BQ3020 binding was found to colocalize to macrophages in atherosclerotic coronary arteries. MicroPET studies demonstrated high uptake of [18F]-BQ3020 in ET(B) receptor-rich tissue, including lung, liver and kidney. The in vivo biodistribution of [18F]-BQ3020 was comparable to that previously obtained for [18F]-ET-1, supporting our hypothesis that the ET(B) receptor plays a significant role in the uptake of ET-1. In conclusion, [18F]-BQ3020 has retained high affinity and selectivity, allowing imaging of ET(B) receptor distributions in vitro and in vivo in human and animal tissue. Furthermore, in vitro data suggest that [18F]-BQ3020 potentially can be used to image atherosclerotic lesions in vivo using PET.

Animals↗
PubMed2005

Identification of culprit lesions after transient ischemic attack by combined 18F fluorodeoxyglucose positron-emission tomography and high-resolution magnetic resonance imaging.

BACKGROUND AND PURPOSE: Carotid endarterectomy is currently guided by angiographic appearance on the assumption that the most stenotic lesion visible at angiography is likely to be the lesion from which future embolic events will arise. However, risk of plaque rupture, the most common cause of atherosclerosis-related thromboembolism, is dictated by the composition of the plaque, in particular the degree of inflammation. Angiography may, therefore, be an unreliable method of identifying vulnerable plaques. In this study, plaque inflammation was quantified before endarterectomy using the combination of 18F fluorodeoxyglucose positron (FDG)-emission tomography (PET) and high-resolution MRI (HRMRI). METHODS: Twelve patients, all of whom had suffered a recent transient ischemic attack, had a severe stenosis in the ipsilateral carotid artery, and were awaiting carotid endarterectomy underwent FDG-PET and HRMRI scanning. A semiquantitative estimate of plaque inflammation was calculated for all of the lesions identified on HRMRI. RESULTS: In 7 of 12 patients (58%), high FDG uptake was seen in the lesion targeted for endarterectomy. In the remaining 5 patients, FDG uptake in the targeted lesion was low. In these 5 patients, 3 had nonstenotic lesions identified on HRMRI that exhibited a high level of FDG uptake. All 3 of the highly inflamed nonstenotic lesions were located in a vascular territory compatible with the patients' presenting symptoms. CONCLUSIONS: Our data suggest that angiography may not always identify the culprit lesion. Combined FDG-PET and HRMRI can assess the degree of inflammation in stenotic and nonstenotic plaques and could potentially be used to identify lesions responsible for embolic events.

Aged↗
PubMed2005

Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification.

Vascular calcification predicts an increased risk for cardiovascular events/mortality in atherosclerosis, diabetes, and ESRD. Serum concentrations of alpha(2)-Heremens-Schmid glycoprotein, commonly referred to as fetuin-A, are reduced in ESRD, a condition associated with an elevated circulating calcium x phosphate product. Mice that lack fetuin-A exhibit extensive soft tissue calcification, which is accelerated on a mineral-rich diet, suggesting that fetuin-A acts to inhibit calcification systemically. Western blot and immunohistochemistry demonstrated that serum-derived fetuin-A co-localized with calcified human vascular smooth muscle cells (VSMC) in vitro and in calcified arteries in vivo. Fetuin-A inhibited in vitro VSMC calcification, induced by elevated concentrations of extracellular mineral ions, in a concentration-dependent manner. This was achieved in part through inhibition of apoptosis and caspase cleavage. Confocal microscopy and electron microscopy-immunogold demonstrated that fetuin-A was internalized by VSMC and concentrated in intracellular vesicles. Subsequently, fetuin-A was secreted via vesicle release from apoptotic and viable VSMC. Vesicles have previously been identified as the nidus for mineral nucleation. The presence of fetuin-A in vesicles abrogated their ability to nucleate basic calcium phosphate. In addition, fetuin-A enhanced phagocytosis of vesicles by VSMC. These observations provide evidence that the uptake of the serum protein fetuin-A by VSMC is a key event in the inhibition of vesicle-mediated VSMC calcification. Strategies aimed at maintaining normal circulating levels of fetuin-A may prove beneficial in patients with ESRD.

Blood Proteins↗
PubMed2005

Nesprins: intracellular scaffolds that maintain cell architecture and coordinate cell function?

Nesprins are a recently discovered family of ubiquitously expressed intracellular proteins. Through alternative transcriptional initiation, termination and splicing, two genes - nesprin-1 and nesprin-2 (also known as syne-1 and syne-2) - give rise to many protein isoforms that vary markedly in size. The largest of these isoforms comprise a C-terminal transmembrane domain (the KLS domain) linked by a spectrin-repeat rod domain to an N-terminal paired, actin-binding, calponin-homology domain. This structure suggests that they are well suited to orchestrate signalling between cell membranes and the cytoskeleton. Other isoforms have variable lengths of this rod domain linked to either end of the protein. Smaller isoforms with the KLS domain are localised at the inner nuclear membrane, where they bind lamin A/C and emerin. Larger nesprin isoforms link the outer nuclear membrane with intracellular organelles and the actin cytoskeleton and are thought to regulate nuclear anchorage and organelle migration. Thus, nesprins might have a variety of fundamental roles in cells, particularly muscle cells where they are highly expressed. We speculate that nesprin mutations might contribute to a broad range of human disease syndromes, including laminopathies.

Animals↗
PubMed2005

Smad7 gene transfer attenuates adventitial cell migration and vascular remodeling after balloon injury.

OBJECTIVE: Migration of adventitial fibroblasts contributes to arterial remodeling after angioplasty. This study used vascular gene transfer of smad7 to investigate whether antagonism of transforming growth factor-beta1 signaling alters luminal loss and adventitial cell migration after balloon injury in rat carotid arteries. METHODS AND RESULTS: Adenoviruses coordinating expression of beta-galactosidase (beta-gal) and smad7 or beta-gal and green fluorescent protein (GFP) were applied to the perivascular surface of common carotid arteries. Balloon injury was performed 4 days after gene transfer, and animals were killed at 3, 7, and 14 days after injury. Uninjured arteries only expressed adventitial beta-gal positive cells; however, after balloon injury in beta-gal- and GFP-transfected arteries, beta-gal-positive cells were observed within the medial layer of vessels and contributed to the population of cells within the neointima at 7 to 14 days. Overexpression of smad7 and beta-gal resulted in a significant reduction in the number of beta-gal-labeled cells in the neointima, concomitant with reduced luminal loss and decreased adventitial collagen content. CONCLUSIONS: We provide the first evidence that vascular smad7 overexpression attenuates remodeling and contribution of adventitial fibroblasts to neointima formation after balloon angioplasty. Smad7 may represent a novel therapeutic target to reduce the incidence of restenosis.

Actins↗
PubMed2005

Imaging the vertebral artery.

Although conventional intraarterial digital subtraction angiography remains the gold standard method for imaging the vertebral artery, noninvasive modalities such as ultrasound, multislice computed tomographic angiography and magnetic resonance angiography are constantly improving and are playing an increasingly important role in diagnosing vertebral artery pathology in clinical practice. This paper reviews the current state of vertebral artery imaging from an evidence-based perspective. Normal anatomy, normal variants and a number of pathological entities such as vertebral atherosclerosis, arterial dissection, arteriovenous fistula, subclavian steal syndrome and vertebrobasilar dolichoectasia are discussed.

Angiography, Digital Subtraction↗
PubMed2005

Nesprin-2 is a multi-isomeric protein that binds lamin and emerin at the nuclear envelope and forms a subcellular network in skeletal muscle.

Nesprin-2 is a multi-isomeric, modular protein composed of variable numbers of spectrin-repeats linked to a C-terminal transmembrane domain and/or to N-terminal paired calponin homology (CH) domains. The smaller isoforms of nesprin-2 co-localize with and bind lamin A and emerin at the inner nuclear envelope (NE). In SW-13 cells, which lack lamin A/C, nesprin-2 epitopes and emerin were both mislocalized and formed aggregates in the endoplasmic reticulum (ER). The larger isoforms and other CH-domain-containing isoforms co-localize with heterochromatin within the nucleus and are also present at the outer NE and in multiple cytoplasmic compartments. Nesprin-2 isoforms relocalize during in vitro muscle differentiation of C2C12 myoblasts to the sarcomere of myotubes. Immunogold electron microscopy using antibodies specific for three different epitopes detected nesprin-2 isoforms at multiple locations including intranuclear foci, both membranes of the NE, mitochondria, sarcomeric structures and plasma membrane foci. In adult skeletal muscle, confocal immunolocalization studies demonstrated that nesprin-2 epitopes were present at the Z-line and were also associated with the sarcoplasmic reticulum (SR) in close apposition to SERCA2. These data suggest that nesprin-2 isoforms form a linking network between organelles and the actin cytoskeleton and thus may be important for maintaining sub-cellular spatial organisation. Moreover, its association at the NE with lamin and emerin, the genes mutated in Emery-Dreifuss muscular dystrophy, suggests a mechanism to explain how disruption of the NE leads to muscle dysfunction.

Actin Cytoskeleton↗
PubMed2005

Imaging of atherosclerosis -- can we predict plaque rupture?

Rupture of so-called vulnerable or unstable atherosclerotic lesions is responsible for a significant proportion of myocardial infarcts and strokes. However, timely identification of such plaques, in order to allow for aggressive local and systemic therapy, remains problematic. In order to address this problem, there is a need to develop techniques that can image the cellular, biochemical, and molecular components that typify the vulnerable plaque. In this article, both techniques that are in current clinical use and those being evaluated in clinical trials are reviewed with regard to their ability to identify unstable lesions at risk of rupture.

Coronary Angiography↗
PubMed2004

Induction, differentiation, and remodeling of blood vessels after transplantation of Bcl-2-transduced endothelial cells.

Implants of collagen-fibronectin gels containing Bcl-2-transduced human umbilical vein endothelial cells (Bcl-2-HUVECs) induce the formation of human endothelial cell (EC)/murine vascular smooth muscle cell (VSMC) chimeric vessels in immunodeficient mice. Microfil casting of the vasculature 60 d after implantation reveals highly branched microvascular networks within the implants that connect with and induce remodeling of conduit vessels arising from the abdominal wall circulation. Approximately 85% of vessels within the implants are lined by Bcl-2-positive human ECs expressing VEGFR1, VEGFR2, and Tie-2, but not integrin alpha(v)beta(3). The human ECs are seated on a well formed human laminin/collagen IV-positive basement membrane, and are surrounded by mouse VSMCs expressing SM-alpha actin, SM myosin, SM22alpha, and calponin, all markers of contractile function. Transmission electron microscopy identified well formed EC-EC junctions, chimeric arterioles with concentric layers of contractile VSMC, chimeric capillaries surrounded by pericytes, and chimeric venules. Bcl-2-HUVEC-lined vessels retain 70-kDa FITC-dextran, but not 3-kDa dextran; local histamine rapidly induces leak of 70-kDa FITC-dextran or India ink. As in skin, TNF induces E-selectin and vascular cell adhesion molecule 1 only on venular ECs, whereas intercellular adhesion molecule-1 is up-regulated on all human ECs. Bcl-2-HUVEC implants are able to engraft within and increase perfusion of ischemic mouse gastrocnemius muscle after femoral artery ligation. These studies show that cultured Bcl-2-HUVECs can differentiate into arterial, venular, and capillary-like ECs when implanted in vivo, and induce arteriogenic remodeling of the local mouse vessels. Our results support the utility of differentiated EC transplantation to treat tissue ischemia.

Animals↗
PubMed2004

Adipocytic differentiation and liver x receptor pathways regulate the accumulation of triacylglycerols in human vascular smooth muscle cells.

Lipid accumulation by vascular smooth muscle cells (VSMC) is a feature of atherosclerotic plaques. In this study we describe two mechanisms whereby human VSMC foam cell formation is driven by de novo synthesis of fatty acids leading to triacylglycerol accumulation in intracellular vacuoles, a process distinct from serum lipoprotein uptake. VSMC cultured in adipogenic differentiation medium accumulated lipids and were induced to express the adipocyte marker genes adipsin, adipocyte fatty acid-binding protein, C/EBPalpha, PPARgamma, and leptin. However, complete adipocyte differentiation was not observed as numerous genes present in mature adipocytes were not detected, and the phenotype was reversible. The rate of lipid accumulation was not affected by PPARgamma agonists, but screening for the effects of other nuclear receptor agonists showed that activation of the liver X receptors (LXR) dramatically promoted lipid accumulation in VSMC. Both LXRalpha and LXRbeta were present in VSMC, and their activation with TO901317 resulted in induction of the lipogenic genes fatty acid synthetase, sterol regulatory element binding protein (SREBP1c), and stearoyl-CoA desaturase. 27-Hydroxycholesterol, an abundant oxysterol synthesized by VSMC acted as an LXR antagonist and, therefore, may have a protective role in preventing foam cell formation. Immunohistochemistry showed that VSMC within atherosclerotic plaques express adipogenic and lipogenic markers, suggesting these pathways are present in vivo. Moreover, the development of an adipogenic phenotype in VSMC is consistent with their known phenotypic plasticity and may contribute to their dysfunction in atherosclerotic plaques and, thus, impinge on plaque growth and stability.

ATP-Binding Cassette Transporters↗
PubMed2004

Short term arterial remodelling in the aortae of cholesterol fed New Zealand white rabbits shown in vivo by high-resolution magnetic resonance imaging - implications for human pathology.

High-resolution, non-invasive imaging methods are required to monitor progression and regression of atherosclerotic plaques. We investigated the use of MRI to measure changes in plaque volume and vessel remodelling during progression and regression of atherosclerosis in New Zealand White rabbits. Atherosclerotic lesions were induced in the abdominal aorta by balloon injury and cholesterol feeding. MR images (2D) of the abdominal aorta were acquired with cardiac and respiratory gating using a fast spin echo sequence with and without fat-suppression. In an initial study on rabbits treated for 30 weeks we imaged the aortae with a spatial resolution of 250x250 micrometers with a slice thickness of 2 mm and achieved a close correlation between MRI-derived measurements and those made on perfusion pressure-fixed histological sections (r(1) = 0.83, slope p(1) < 0.01). We subsequently imaged 18 rabbits before and periodically during 12 weeks of cholesterol feeding (progression) followed by 12 weeks on normal diet (regression). Aortic wall (atherosclerotic lesion) volume increased significantly during progression and decreased during regression. In contrast, lumen volume increased during progression and did not change during regression. In conclusion, this study confirms that non-invasive, high-resolution MRI can be used to monitor progression and regression of atherosclerosis, each within 3 months and shows, for the first time in a short-term model, that positive remodelling occurs early during progression and persists through regression of atherosclerotic lesions.

Animals↗
PubMed2004

Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.

Patients with ESRD have a high circulating calcium (Ca) x phosphate (P) product and develop extensive vascular calcification that may contribute to their high cardiovascular morbidity. However, the cellular mechanisms underlying vascular calcification in this context are poorly understood. In an in vitro model, elevated Ca or P induced human vascular smooth muscle cell (VSMC) calcification independently and synergistically, a process that was potently inhibited by serum. Calcification was initiated by release from living VSMC of membrane-bound matrix vesicles (MV) and also by apoptotic bodies from dying cells. Vesicles released by VSMC after prolonged exposure to Ca and P contained preformed basic calcium phosphate and calcified extensively. However, vesicles released in the presence of serum did not contain basic calcium phosphate, co-purified with the mineralization inhibitor fetuin-A and calcified minimally. Importantly, MV released under normal physiologic conditions did not calcify, and VSMC were also able to inhibit the spontaneous precipitation of Ca and P in solution. The potent mineralization inhibitor matrix Gla protein was found to be present in MV, and pretreatment of VSMC with warfarin markedly enhanced vesicle calcification. These data suggest that in the context of raised Ca and P, vascular calcification is a modifiable, cell-mediated process regulated by vesicle release. These vesicles contain mineralization inhibitors derived from VSMC and serum, and perturbation of the production or function of these inhibitors would lead to accelerated vascular calcification.

Adolescent↗
PubMed2004

Molecular and metabolic imaging of atherosclerosis.

Atherosclerosis is a systemic disease that affects most major arteries of the body and is the most common cause of premature death in the western world. It develops slowly and often asymptomatically, so that for many patients its first manifestation is sudden cardiac death, stroke, or myocardial infarction. The current gold standard for imaging atherosclerosis is x-ray angiography. However, recent advances in understanding of the pathobiology of atherosclerosis have highlighted the inadequacies of this technique and the need for better imaging approaches. The purpose of this article is to briefly outline the biology of atherosclerosis and to review the techniques available to image it, concentrating specifically on those that detect metabolic or inflammatory changes within the atherosclerotic plaque.

Arteriosclerosis↗
PubMed2003

Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms.

OBJECTIVE: We have previously shown that human macrophages induce human plaque vascular smooth muscle cell (VSMC) apoptosis by cell-cell proximity, Fas-L, and nitric oxide (NO), thereby predisposing to plaque rupture. This study sought to analyze whether tumor necrosis factor-alpha (TNF-alpha) contributes additionally to macrophage-induced VSMC apoptosis. METHODS AND RESULTS: Macrophage-induced VSMC apoptosis was examined in direct coculture. Antagonistic antibodies to TNF-receptor (R1) inhibited VSMC apoptosis, and preincubation of monocytes and VSMCs indicated that TNF-R1 on both cell types contributed to macrophage-induced VSMC apoptosis. Correspondingly, both monocytes and VSMCs expressed TNF-R1, and macrophages expressed cell surface TNF-alpha. Two NO donors upregulated VSMC surface TNF-R1, and exogenous TNF-alpha induced VSMC apoptosis synergistically with the NO donor diethylenetriamine/NO, indicating that NO sensitizes VSMCs to TNF-alpha. Neutralizing anti-TNF-R1 antibodies inhibited macrophage activation assessed by Fas-L expression and NO secretion. CONCLUSIONS: TNF-alpha promotes macrophage-induced VSMC apoptosis by autocrine and direct pathways.

Antibodies, Blocking↗