Biomedical subjects

Sarah J George

Publications and source records attributed to Sarah J George.

17 recordsLinked to original sources

PubMed2006

Regulation of smooth muscle cell proliferation by beta-catenin/T-cell factor signaling involves modulation of cyclin D1 and p21 expression.

We previously observed that stimulation of vascular smooth muscle cell (VSMC) proliferation with growth factors is associated with dismantling of cadherin junctions and nuclear translocation of beta-catenin. In this study we demonstrate directly that growth factors stimulate beta-catenin/T-cell factor (TCF) signaling in primary VSMCs. To determine whether beta-catenin/TCF signaling regulates VSMC proliferation via modulation of the beta-catenin/TCF responsive cell cycle genes, cyclin D1 and p21, we inhibited beta-catenin/TCF signaling by adenoviral-mediated over-expression of N-Cadherin, ICAT (an endogenous inhibitor of beta-catenin/TCF signaling), or a dominant negative (dn) mutant of TCF-4. N-cadherin, ICAT or dnTCF-4 over-expression significantly reduced proliferation of isolated human VSMCs by approximately 55%, 80%, and 45% respectively. Similar effects were observed in human saphenous vein medial segments where proliferation was reduced by approximately 55%. Transfection of dnTCF-4 in the ISS10 human VSMC line significantly lowered TCF and cyclin D1 reporter activity but significantly elevated p21 reporter activity, indicating regulation of these genes by beta-catenin/TCF signaling. In support of this, over-expression of N-cadherin, ICAT or dnTCF-4 in isolated human VSMCs significantly lowered levels of cyclin D1 mRNA and protein levels. In contrast, over-expression of N-Cadherin, ICAT or dnTCF4 significantly elevated p21 mRNA and protein levels. In summary, we have demonstrated that increasing N-cadherin and inhibiting beta-catenin/TCF signaling reduces VSMC proliferation, decreases the expression of cyclin D1 and increases levels of the cell cycle inhibitor, p21. We therefore suggest that the N-cadherin and beta-catenin/TCF signaling pathway is a key modulator of VSMC proliferation via regulation of these 2 beta-catenin/TCF responsive genes.

Aorta↗

PubMed2006

Short- and long-term effects of cytochalasin D, paclitaxel and rapamycin on wall thickening in experimental porcine vein grafts.

OBJECTIVES: Neointima formation and wall thickening caused by smooth muscle cell proliferation compromise long-term patency of human aorto-coronary vein-grafts. We investigated short- and long-term effects of anti-proliferative pharmacological agents on experimental pig vein-grafts with similar dimensions and kinetics to human coronary grafts. METHODS AND RESULTS: Saphenous veins were treated for 1 h ex vivo with vehicle or concentrations of cytochalasin D, paclitaxel or rapamycin found to be anti-proliferative in preliminary studies. Vehicle and treated veins were implanted contralaterally, end-to-end into the carotid arteries of pigs. Cytochalasin D 2.5 mug/ml non-significantly reduced neointima formation in 4-week vein-grafts (mean+/-standard error, 2.5+/-0.6 vs. 3.3+/-0.6 mm2, n = 10, p = NS), whilst paclitaxel 10 microM produced significant inhibition (1.7+/-0.2 vs. 3.0+/-0.3 mm2, n = 8, p < 0.01) as did rapamycin 0.1 mg/ml (0.6+/-0.3 vs. 1.7+/-0.5 mm(2), n = 8, p < 0.02). Similar effects were found on total wall cross-sectional area but medial area was unaffected. PCNA staining of 1-week vein grafts confirmed in vivo anti-proliferative effects of paclitaxel (21+/-2 vs. 36+/-3%, n = 5, p < 0.01) and rapamycin (32+/-1 vs. 57+/-6%, n = 6, p < 0.005); neither agent stimulated loss of endothelium at these concentrations. Neointima and total wall area increased significantly between 4- and 12-weeks in all vein-grafts such that there was no longer a significant effect on neointima formation of either paclitaxel (7.5+/-1.3 vs. 8.9+/-1.9 mm2 in control, n = 5, p = NS) or rapamycin (6.0+/-0.9 vs. 7.9+/-1.1 mm2 in control, n = 9, p = NS) or on total wall area in 12-week grafts. CONCLUSIONS: Pre-treatment of saphenous vein with anti-proliferative agents paclitaxel or rapamycin reduced neointima and total wall area after 4 weeks but continued growth abolished differences by 12 weeks. These results may help to understand the failure of clinical studies using anti-proliferative treatments in vein-grafts.

Animals↗

PubMed2006

Suppression of atherosclerotic plaque progression and instability by tissue inhibitor of metalloproteinase-2: involvement of macrophage migration and apoptosis.

BACKGROUND: Matrix metalloproteinase (MMP)-associated extracellular matrix degradation is thought to contribute to the progression and rupture of atherosclerotic plaques. However, direct evidence of this concept remains elusive. We hypothesized that overexpression of tissue inhibitor of metalloproteinase (TIMP)-1 or TIMP-2 would attenuate atherosclerotic plaque development and instability in high fat-fed apolipoprotein E-knockout (apoE(-/-)) mice. METHODS AND RESULTS: Seventy male apoE(-/-) mice (n=10/group) fed a high-fat diet for 7 weeks were injected intravenously with first-generation adenoviruses expressing the gene for human TIMP-1 (RAdTIMP-1) or TIMP-2 (RAdTIMP-2) or a control adenovirus (RAd66) and were fed a high-fat diet for a further 4 weeks. Analysis of brachiocephalic artery plaques revealed that RAdTIMP-2 but not RAdTIMP-1 infection resulted in a marked reduction (48+/-13%, P<0.05) in lesion area compared with that in control animals. Markers associated with plaque instability, assessed by smooth muscle cell and macrophage content and the presence of buried fibrous caps, were significantly reduced by RAdTIMP-2. Effects on lesion size were not sustained with first-generation adenoviruses, but murine TIMP-2 overexpression mediated by helper-dependent adenoviral vectors exerted significant effects on plaques assessed 11 weeks after infection. In an attempt to determine the mechanism of action, we treated macrophages and macrophage-derived foam cells with exogenous TIMP-2 in vitro. TIMP-2 significantly inhibited migration and apoptosis of macrophages and foam cells, whereas TIMP-1 failed to exert similar effects. CONCLUSIONS: Overexpression of TIMP-2 but not TIMP-1 inhibits atherosclerotic plaque development and destabilisation, possibly through modulation of macrophage and foam cell behavior. Helper-dependent adenovirus technology is required for these effects to be maintained long term.

Adenoviridae↗

PubMed2006

Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability.

OBJECTIVE: Matrix metalloproteinases (MMPs) form a large family of enzymes that collectively can degrade all components of the extracellular matrix, and there is widespread interest in developing MMP inhibitors for the prevention of atherosclerotic plaque rupture. We have therefore investigated the effects of a broad-spectrum MMP inhibitor, RS-130830, on plaque development and stability. This compound inhibits a wide range of MMPs at concentrations below 20 nmol/L. METHODS: Apolipoprotein E knockout mice were fed a Western diet. Dietary administration of RS-130830 commenced at the same time as fat-feeding and continued for 8, 12, 26 or 36 weeks. To investigate the effect of RS-130830 on established plaques, mice were fed high-fat diet for 16 weeks before initiation of drug treatment and were terminated 20 weeks after this. RESULTS: Broad-spectrum MMP inhibition was associated with a significant increase in plaque area, but there was no change in the incidence of plaque rupture. There were unfavourable changes in phenotypic characteristics associated with plaque instability, such as an increased lipid content and decreased collagen content. CONCLUSIONS: These data suggest that broad-spectrum MMP inhibition RS-130830 does not have a beneficial effect on atherosclerosis in the apolipoprotein E knockout mouse model, and indicate that more selective compounds would be preferable.

Animals↗

PubMed2006

Gene therapy and coronary artery bypass grafting: current perspectives.

The early success of coronary artery bypass grafting (CABG) is limited by disappointing long-term patency rates of autologous saphenous vein grafts. Because current pharmacological interventions have only limited impact on vein graft patency rates, there remains a clear clinical need for effective agents to prevent failure of vein grafts in the long term. Gene therapy in vein grafts has great potential as gene delivery can be achieved ex vivo at the time of cardiac surgery, allowing transgene expression to occur rapidly post-grafting within the acute phase of vein graft remodelling. A variety of therapeutic strategies have been tested in a range of preclinical models, although to date, these have not advanced to Inhuman trials, except in the setting of adjunctive angiogenesis for improved revascularization (phase 1). Clinical translation is warranted to investigate the potential of gene therapy to improve CABG patency rates in the long term.

Clinical Trials as Topic↗

PubMed2005

Regulation of vascular smooth muscle cell proliferation, migration and death by heparan sulfate 6-O-endosulfatase1.

Migration, proliferation and death of vascular smooth muscle cells (VSMC) are important events in vascular pathology regulated by heparan sulfate proteoglycans and hence potentially by cell surface HS 6-O-endosulfatase1 (sulf1). Sulf1 mRNA expression was increased in cultured VSMC compared to rat aorta. Furthermore, adenovirus mediated overexpression of quail sulf1 decreased adhesion, and increased proliferation and apoptosis of VSMC. Overexpression of a dominant negative variant also decreased adhesion of VSMC and increased proliferation, apoptosis, migration and chemotaxis of VSMC. Our results imply that only normal levels of 6-O-sulfation maintained by sulf1 are optimal for several functions of VSMC.

Adenoviridae↗

PubMed2005

Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries.

Matrix metalloproteinases (MMPs) are thought to be involved in the growth, destabilization, and eventual rupture of atherosclerotic lesions. Using the mouse brachiocephalic artery model of plaque instability, we compared apolipoprotein E (apoE)/MMP-3, apoE/MMP-7, apoE/MMP-9, and apoE/MMP-12 double knockouts with their age-, strain-, and sex-matched apoE single knockout controls. Brachiocephalic artery plaques were significantly larger in apoE/MMP-3 and apoE/MMP-9 double knockouts than in controls. The number of buried fibrous layers was also significantly higher in the double knockouts, and both knockouts exhibited cellular compositional changes indicative of an unstable plaque phenotype. Conversely, lesion size and buried fibrous layers were reduced in apoE/MMP-12 double knockouts compared with controls, and double knockouts had increased smooth muscle cell and reduced macrophage content in the plaque, indicative of a stable plaque phenotype. ApoE/MMP-7 double knockout plaques contained significantly more smooth muscle cells than controls, but neither lesion size nor features of stability were altered in these animals. Hence, MMP-3 and MMP-9 appear normally to play protective roles, limiting plaque growth and promoting a stable plaque phenotype. MMP-12 supports lesion expansion and destabilization. MMP-7 has no effect on plaque growth or stability, although it is associated with reduced smooth muscle cell content in plaques. These data demonstrate that MMPs are directly involved in atherosclerotic plaque destabilization and clearly show that members of the MMP family have widely differing effects on atherogenesis.

Animals↗

PubMed2005

Transforming growth factor-beta is activated by plasmin and inhibits smooth muscle cell death in human saphenous vein.

BACKGROUND: The effect of activation of endogenous transforming growth factor-beta (TGF-beta) on smooth muscle cell apoptosis was assessed in human saphenous vein. METHODS: Segments of human saphenous vein, obtained at the time of bypass graft surgery, were cultured for 14 days. During this time, smooth muscle cells accumulated in the intima as a result of proliferation and migration, partly counterbalanced by apoptotic cell death. RESULTS: Addition of exogenous TGF-beta(1) had no effect on smooth muscle cell proliferation or apoptosis. However, antibody neutralization of endogenous TGF-beta(1) caused significant increases in smooth muscle cell death in the media and intima without any change in proliferation. A plasmin inhibitor (alpha-N-acetyl-L-lysine methyl ester), a specific urokinase-type plasminogen activator (uPA) inhibitor (amiloride) and an anti-catalytic anti-uPA antibody all caused decreases in the tissue content of active TGF-beta and increases in smooth muscle cell death in the media and intima. CONCLUSIONS: These data suggest that the amount of TGF-beta in human saphenous vein is sufficient, when in the active form, to protect smooth muscle cells against apoptosis. Adding exogenous TGF-beta(1) has no beneficial effect, but decreasing the amount of active TGF-beta causes smooth muscle cells to undergo apoptosis. Plasmin, generated by uPA, appears to be an important activator of endogenous latent TGF-beta.

Amiloride↗

PubMed2005

N-cadherin-dependent cell-cell contacts promote human saphenous vein smooth muscle cell survival.

OBJECTIVE: Vascular smooth muscle cell (VSMC) apoptosis is thought to contribute to atherosclerotic plaque instability. Cadherin mediates calcium-dependent homophilic cell-cell contact. We studied the role of N-cadherin in VSMC apoptosis. METHODS AND RESULTS: Human saphenous vein VSMCs were grown in agarose-coated wells to allow cadherin-mediated aggregate formation. Cell death and apoptosis were determined after disruption of cadherins using several approaches (n> or =3 per approach). Calcium removal from culture medium or addition of nonspecific cadherin antagonist peptides significantly decreased aggregate formation and increased cell death by apoptosis (34+/-6% versus 75+/-1% and 19+/-1% versus 40+/-5%, respectively; P<0.05). Specific inhibition of N-cadherin using antagonists and neutralizing antibodies similarly increased apoptosis. Supporting this, overexpression of full-length N-cadherin significantly reduced VSMC apoptosis from 44+/-10% to 20+/-3% (P<0.05), whereas abolishing N-cadherin expression by overexpression of a dominant-negative N-cadherin significantly, even in the presence of cell-matrix contacts, increased apoptosis from 9+/-2% to 50+/-1% (P<0.05). Interestingly, cell-cell contacts provided a similar degree of protection from apoptosis to cell-matrix contacts. Finally, N-cadherin-mediated cell-cell contacts initiated anti-apoptotic signaling by increasing Akt and Bad phosphorylation. CONCLUSIONS: Our results indicate that VSMC survival is dependent on N-cadherin-mediated cell-cell contacts, which could be important in the context of plaque instability.

Antibodies↗

PubMed2004

Targeted inhibition of human collagenase-3 (MMP-13) expression inhibits squamous cell carcinoma growth in vivo.

Squamous cell carcinomas (SCCs) of the head and neck are characterized by a high tendency for local invasion and metastasis to lymph nodes. Collagenase-3 (MMP-13) is specifically expressed by tumor cells in SCCs of the head and neck and its expression correlates with their invasion capacity. To specifically examine the role of MMP-13 in the growth and invasion of SCC, we constructed a hammerhead ribozyme targeted against human MMP-13 mRNA. The anti-MMP-13 ribozyme effectively cleaved MMP-13 transcripts in vitro. Adenoviral delivery of the anti-MMP-13 ribozyme to cutaneous metastatic SCC cells in culture resulted in potent and specific inhibition of the production of proMMP-13 and markedly suppressed invasion of SCC cells through Matrigel. In addition, adenoviral delivery of anti-MMP-13 ribozyme promoted apoptosis in SCC cells within 72 h. Intratumoral injection of anti-MMP-13 ribozyme coding adenovirus into human SCC xenografts established in SCID mice potently suppressed tumor growth, inhibited MMP-13 expression and gelatinolytic activity and reduced the number of proliferating cells within the tumors. These results provide evidence for an important role for MMP-13 in SCC growth and invasion and identify MMP-13 as a promising target for ribozyme-based therapy of SCC in vivo.

Adenoviridae↗

PubMed2004

R-cadherin:beta-catenin complex and its association with vascular smooth muscle cell proliferation.

OBJECTIVE: Vascular smooth muscle cell (VSMC) proliferation is an important component of atherosclerosis, restenosis after angioplasty and stent placement, and vein graft failure. Outside-in signaling from the cadherin:beta-catenin complex can increase transcription of the cell-cycle gene cyclin D1; however, its role in VSMC proliferation has only recently been considered. METHODS AND RESULTS: We examined the involvement of R-cadherin and beta-catenin in VSMC proliferation in balloon-injured carotid arteries in vivo and aortic rings in vitro. The number of medial VSMCs positive for R-cadherin was significantly reduced by 32%+/-5%, 52%+/-10%, and 23%+/-2% at 0.25, 24, and 48 hours after injury in vivo, respectively. These changes in cadherin expression coincided with the detection of nuclear beta-catenin and elevated cyclin D1 expression. Furthermore, loss of R-cadherin expression was associated with medial VSMC proliferation. Inhibition of classical cadherin function with a HAV peptide and R-cadherin neutralizing antibodies significantly increased proliferation by 4.3+/-1.0-fold and 4.1+/-0.98-fold, and increased the number of cells with beta-catenin in the nucleus and expressing cyclin D1 in aortic rings. CONCLUSIONS: These results suggest that R-cadherin expression and beta-catenin signaling may be associated with increased cyclin D1 expression and VSMC proliferation and may therefore play an important role in vascular disease.

Animals↗

PubMed2004

Overexpression of p53 increases lumen size and blocks neointima formation in porcine interposition vein grafts.

Patency rates for autologous saphenous vein (SV) conduits used in coronary artery bypass grafts remain poor. Patients with failed grafts are difficult to treat with subsequent interventions, necessitating the development of innovative therapies. Previous studies have suggested that induction of smooth muscle cell (SMC) apoptosis may reduce neointima formation. We overexpressed the proapoptotic gene p53 at the lumenal surface of SV grafts using adenoviral (Ad)-mediated gene transfer in porcine SVs prior to grafting in vivo and analyzed at 7 and 28 days (n = 6 and 7 per group, respectively). p53 overexpression induced a significant upregulation in apoptosis (4 +/- 0.6% for Adp53-infected grafts vs 0.6 +/- 0.1% for Adbeta-gal-infected grafts) and reduced neointimal proliferation by 28 +/- 1% at day 7 postinfection. Adp53-infected grafts had significantly greater lumenal areas than controls at both time points (4.8 +/- 0.6 mm2 vs 2.9 +/- 0.5 mm2 and 10.0 +/- 2.5 mm2 vs 4.2 +/- 1.2 mm2 at 7 and 28 days, respectively). Total graft areas were also increased at 28 days by p53, indicating positive vessel remodeling. Additionally, the thickening of the neointima was significantly reduced by 68 +/- 22% and 28 +/- 3% by p53 overexpression at day 7 and 28, respectively. Importantly, phenotypic changes were maintained at 3 months. Induction of SMC apoptosis by transient p53 overexpression positively influenced vein graft remodeling.

Adenoviridae↗

PubMed2003

Relationship between type IV collagen degradation, metalloproteinase activity and smooth muscle cell migration and proliferation in cultured human saphenous vein.

The relationship between degradation of basement membranes, metalloproteinase (MMP) activity and smooth muscle cell (SMC) migration and proliferation has not been previously investigated in any intervention study. We used adenoviral overexpression of tissue inhibitors of metalloproteinases (TIMPs) in cultured human saphenous veins. By immunocytochemistry, the percentage of medial SMC surrounded by basement membrane type IV collagen (Coll-IV) decreased from 93+/-1 to 77+/-4% and 82+/-1% (n=18, both P<0.001) after 7 and 14 days of culture, respectively, while all SMC that migrated to the neointima lacked Coll-IV. Overexpression of TIMP-1 or TIMP-3 significantly increased the percentage of medial SMC surrounded by Coll-IV (94+/-2 or 98+/-2%, respectively, both P<0.01 vs. no treatment) and decreased the number of neointimal SMC. Some 44+/-18 and 30+/-6%, respectively, of BrdU or PCNA labeled medial SMC remained surrounded by type IV collagen and this was not affected by overexpression of TIMP-1 or TIMP-3. We conclude that MMPs mediate loss of basement membrane and this is closely related to SMC migration. SMC proliferation does not require complete basement membrane degradation, which itself does not require MMPs in proliferating SMC.

Adenoviridae↗

PubMed2003

Dismantling of cadherin-mediated cell-cell contacts modulates smooth muscle cell proliferation.

Proliferation of vascular smooth muscle cells (VSMCs) contributes to intimal thickening during atherosclerosis and restenosis. The cadherins are transmembrane proteins, which form cell-cell contacts and may regulate VSMC proliferation. In this study, N-cadherin protein concentration was significantly reduced by stimulation of proliferation with fetal calf serum (FCS) and platelet-derived growth factor-BB (PDGF-BB) in human saphenous vein VSMCs. Furthermore, overexpression of a truncated N-cadherin, which acts as a dominant-negative increased VSMC proliferation. The amount of an extracellular fragment of N-cadherin (approximately 90 kDa) in the media after 24 hours was increased by 12-fold by FCS and 11-fold by PDGF-BB, suggesting that N-cadherin levels are regulated by proteolytic shedding. Incubation with a synthetic metalloproteinase inhibitor or adenoviral overexpression of the endogenous tissue inhibitors of metalloproteinases (TIMPs) demonstrated that metalloproteinase activity was responsible in part for this proteolysis. Although total levels of beta-catenin protein were not affected, beta-catenin was translocated to the nucleus after stimulation with FCS and PDGF-BB. Our data indicates cadherin-mediated cell-cell contacts modulate proliferation in VSMCs. Furthermore, disruption of N-cadherin cell-cell contacts mediated in part by metalloproteinase activity occurs during VSMC proliferation, releasing beta-catenin and possibly inducing beta-catenin-mediated intracellular signaling.

Animals↗

PubMed2003

Third-generation lentivirus vectors efficiently transduce and phenotypically modify vascular cells: implications for gene therapy.

Grafting of saphenous vein (SV) conduits into the arterial circulation triggers a number of adaptive pathological changes characterized by progressive medial thickening, neointima formation and accelerated atheroma. Previous studies have shown that modification of vein graft biology is possible by adenovirus (Ad)-mediated gene transfer, although gene expression is transient. Advancement of vascular gene therapy to the clinic is compromised by the lack of safe and efficient vector systems that provide sustained therapeutic gene delivery to the vasculature. Due to inadequacies of both Ad and adeno-associated virus (AAV) serotype-2 (AAV-2) systems, we have evaluated gene delivery to endothelial cells (ECs) and smooth muscle cells (SMCs) using alternate AAV serotypes and a third-generation vesicular stomatis virus glycoprotein-pseudotyped lentiviral system. Transduction of both primary human SV EC and SMC was lower using all alternate AAV serotypes compared to AAV-2. However, transduction of both cell types by lentivirus was efficient even at clinically relevant exposure times (15 min), was without toxicity and was promoter sensitive. Transduction levels at lower doses were further enhanced with the addition of the surfactant Poloxamer-407 (P-407). Direct comparison with Ad and AAV-2 confirmed the unique potential for this system. Moreover, we constructed and overexpressed the therapeutic gene tissue inhibitor of metalloproteinase-3 (TIMP-3) using lentivirus and demonstrated transgene production comparable to Ad with concomitant blockade of SMC migration and induction of cell death. We have demonstrated for the first time the potential for third-generation lentiviral vectors, but not alternate AAV serotypes, as efficient vascular gene delivery vectors.

Cardiovascular System↗

PubMed2002

Antitumor activity and bystander effect of adenovirally delivered tissue inhibitor of metalloproteinases-3.

We have studied the effect of a newly identified tumor suppressor tissue inhibitor of metalloproteinases- 3 (TIMP-3) on the growth of human melanoma and squamous-cell carcinoma (SCC). Adenoviral delivery of the TIMP-3 gene to human melanoma (A2058) and SCC (UT-SCC-7) cells ex vivo inhibited tumorigenesis after subcutaneous (s.c.) injection of the infected cells into SCID/SCID mice. Three daily consecutive intratumoral injections of 1.4x10(9) plaque-forming units (pfu) of TIMP-3 adenovirus (RAdTIMP-3) inhibited the growth of preestablished melanoma and SCC xenografts in SCID/SCID mice, whereas growth of control virus-injected tumors was not affected. The antitumor effect of RAdTIMP-3 was obtained with in vivo adenoviral transduction efficiency of 8-10%, and it was more potent than that of adenovirally delivered p53. Adenovirusmediated expression of TIMP-3 potently reduced gelatinolytic activity, increased the number of apoptotic cells, and inhibited vascularization of melanomas. Escalation of the adenoviral dose to three rounds of three daily consecutive injections with 1.4x10(9) pfu of RAdTIMP-3 every 6 days entirely inhibited growth of injected melanomas for 32 days. Mixing RAdTIMP-3-infected A2058 cells with uninfected cells in 1:1 ratio in culture resulted in death of all cells in 96 hours. Adenovirally delivered TIMP-3 was also expressed by A2058 cells in soluble form into the culture medium, where it exerted a cytotoxic effect on uninfected A2058 cell cultures after relocating to the cell layer. These results identify TIMP-3 as a novel type of secreted tumor suppressor, which has antiinvasive, antiangiogenic, and proapoptotic effects in vivo, and which displays a potent bystander effect validating further exploration of its applicability in human cancer gene therapy.

Adenoviridae↗

PubMed2002

Gene transfer to the vasculature: historical perspective and implication for future research objectives.

Cardiovascular diseases are a major cause of fatality, disability, and economic burden in Western civilization. Although the pharmaceutical industry has delivered a plethora of drugs for treatment of diverse cardiovascular complaints, there remain many conditions for which pharmacological regimens are either nonexistent or largely ineffective. In contrast, remarkable progress has been made in the field of vascular gene transfer in the last decade. The vast majority of studies are preclinical, although a number of high profile vascular gene therapy clinical trials are in progress. In principle, vascular gene therapy represents an unprecedented opportunity to treat a host of cardiovascular diseases in humans although many scientific, clinical, and ethical obstacles remain. Here we discuss the rapid progress in preclinical vascular gene therapy, highlight the most appropriate gene delivery vectors, and discuss the advances toward the ultimate goal of an efficient and safe gene therapy for diverse cardiovascular diseases.

Blood Vessels↗