2011 Vascular Research Initiatives Conference: basic foundations of translational research in vascular disease

Abstract

The Vascular Research Initiatives Conference (VRIC) is an annual conference organized by the Society for Vascular Surgery (SVS). The 2011 VRIC was held in Chicago (IL, USA) to precede and coincide with the first day of the meeting of the Council on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) of the American Heart Association. The event is designed to present world class vascular research results, encourage collaboration between vascular surgeons and basic scientists in related disciplines, as well as to stimulate interest in research among aspiring academic vascular surgeons. The 2011 VRIC featured plenary sessions addressing peripheral arterial disease, vascular endothelium and thrombosis, aneurysms, and stem cells and tissue engineering. Recipients of the SVS partner grants with the National Institutes of Health K08 awardees presented their progress reports, and keynote addresses were given by Linda Graham and Frank LoGerfo.

The Vascular Research Initiatives Conference (VRIC) is an annual conference organized by the Society for Vascular Surgery (SVS) that has developed and grown from the first Research Initiatives Conference established in 1986 [1,2]. The VRIC is now in its third year in the current format that precedes and coincides with the first day of the annual meeting of the council on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) of the American Heart Association (AHA), a conference established in 2000. This meeting’s purpose is to present state-of-the-art science to encourage interactions and collaborations between vascular surgeon investigators and scientists from other related disciplines. A second important objective of the VRIC is to stimulate interest in research among aspiring vascular surgeons.

The VRIC is expanding and increasing its vitality through the partnership of the SVS and the AHA; the integrated program was developed through a year-long collaboration of the VRIC course director Alan Dardik (SVS) with the ATVB Program Committee co-chairs Robert Hegele and Murray W Huff (AHA). The merger of the VRIC and ATVB conferences highlights the longstanding tradition, relevance and success of both meetings and emphasizes the importance of the collaboration between the formerly separate entities. Evidence of broad acceptance of the merger includes record-breaking numbers of abstracts submitted, increased meeting attendance, and increased number of non-SVS members present at the VRIC meeting. In addition, Steven Lentz (AHA) and Alan Dardik (SVS) recorded a video discussing the highlights and importance of the merged meeting that was displayed at the AHA and SVS meeting and on YouTube [101].

Topics comprising the VRIC main session included peripheral arterial disease, vascular endothelium and thrombosis, aneurysms, and stem cells and tissue engineering, all of which were jointly comoderated by VRIC and ATVB program committee members. The second day of programming included ATVB conference sessions that are planned in a coordinated fashion between the SVS and AHA program committees, including the jointly sponsored SVS–AHA session on vascular development, differentiation, regeneration, angiogenesis, and other ATVB conference sessions that were jointly coordinated, such as the session on vein graft biology, as well as a joint poster session.

Keynote addresses & awardee reports

Among the highlights of this year’s VRIC were the keynote addresses given by invited speakers Linda M Graham (Cleveland Clinic, OH, USA) and Frank W LoGerfo (Harvard Medical School, MA, USA). Graham discussed her groundbreaking decades-long work as a surgeon–scientist elucidating the regulation of endothelial healing. Graham described how the regulators of endothelial healing are often inhibitory in action, including reactive oxygen species, changes in membrane fluidity, and alterations in cell polarity through the opening of calcium-gated ion channels. In doing so, Graham discussed her extensive studies on the TRPC-5 and -6 molecules, their interactions with oxidized lipids and cholesterol, and their impact on endothelial cell migration. LoGerfo, in his talk on the vein graft response to implantation injury, reminded the attendees to respect the complexity of vascular molecular processes. Presenting bioinformatics data derived from a canine vein graft model, he demonstrated variations in the populations of gene responses that occur from 2 and 12 h to 30 days after surgery; however, many of the potential targets of mechanistic importance represent essential proteins with highly detrimental results when silenced. Current technology is effective in defining the transcriptome response to injury, he concluded, but much work needs to be done in both selecting silencing targets and in the delivery of these agents to allow control of the targets of interest.

In addition, the VRIC served as a forum for the recipients of the SVS partner grants with the National Institutes of Health K08 awardees to present their progress reports. Matthew J Eagleton (Cleveland Clinic) described altered phosphorylation levels of STAT proteins related to matrix metalloproteinase expression in aortic aneurysm formation. Interestingly, these altered phosphorylation ratios of STAT protein colocalized to macrophages and CD68⁺ cells in the adventitia, further implicating inflammation in the pathogenesis of abdominal aortic aneurysms (AAAs). Christopher L Skelly (University of Chicago, IL, USA) presented his data that utilize a modified herpes simplex virus-1 as therapy for the treatment of neointimal hyperplasia. By targeting MEK in dividing cells for cytoreduction, Skelly presented in vivo data showing a dose dependency of effect on graft wall thickness, with the greatest localization occurring in the smooth muscle cells of the graft. This novel work may suggest alternate strategies to control vein graft neointimal hyperplasia, after the disappointing failures of E2F-decoy tested in the PREVENT III and IV trials [3,4].

Plenary sessions

All of the VRIC conference plenary sessions, as well as the breakfast, lunch and reception, are organized to promote substantial interaction between the presenters and the attendees. The first plenary session focused on peripheral arterial disease and was comoderated by Melina Kibbe (SVS) and Debra Newman (AHA). Brian C Cooley (Medical College of Wisconsin, WI, USA) presented data that demonstrated that smooth muscle cells found in lesions of neointimal hyperplasia can largely be traced to the transdifferentiation of cells originating from the endothelium; this sophisticated work used a smooth-muscle cell specific conditional transgenic reporter in his mouse external-jugular-vein-to-femoral-artery interposition graft model. Transdifferentiation of endothelium to a smooth-muscle cell phenotype was found to be mediated by the action of TGF-β. Dhiraj Joshi (Royal Free Hospital, London, UK), reported elevated expression of erythropoietin receptors in skeletal muscles in the setting of critical limb ischemia, and that a derivative cleaved peptide of erythropoietin, ARA 290, decreased inflammation to provide a tissue protective effect. Chandler Long (Watkins Laboratory at the Massachusetts General Hospital, MA, USA) described how PARP inhibition ameliorated muscle fiber injury during ischemia-reperfusion in a diabetic mouse model, independently of inflammation or ATP level. The final talk was delivered by Zhihua Jiang, PhD, from the University of Florida; he reiterated the importance of systemic treatment for anti-MCP-1/CCR2 targeted therapies, as cells both extrinsic and intrinsic to vein graft walls are able to produce sufficient MCP-1 to accelerate neointimal hyperplasia.

Vascular endothelium and thrombosis were the topics for the second morning session that was comoderated by Gilbert Upchurch (SVS) and Steven Lentz (AHA). Kenneth R Ziegler (Dardik Laboratory, Yale University, CT, USA) presented evidence suggesting a novel role for β-1 integrins on endothelial cells as upstream regulators of Eph-B4-mediated vein graft adaptation; this finding links hemodynamic forces experienced by the vein graft wall directly to biochemical changes responsible for wall thickening. Andrea L Nestor Kalinoski (University of Toledo, OH, USA) described her work confirming a genetic component controlling extracellular matrix organization and arterial elasticity in a hypertensive rat model; the impact on the vasoreactivity of these arteries by architectural remodeling could aid in addressing the deleterious effects of arterial stiffening in cardiovascular disease. Ryan O Lakin (Cleveland Clinic), generated numerous questions from the audience after presenting his data suggesting an improvement in endothelial function in both normal and atherosclerotic lower extremity arteries in humans after supplementation with L-arginine. George E Havelka (Kibbe Laboratory, Northwestern University, IL, USA), discussed CK2, a ubiquitous enzyme that is known as a potent inducer of cell proliferation, and its regulation by sex, nitric oxide and the presence of sex hormones after carotid artery injury in rats. Alice Chanakira (University of Minnesota, MN, USA) demonstrated that smooth muscle cells experienced significant migration in response to hypoxia, though those derived from veins migrated at a greater velocity than those derived from arteries, and that this migration is dependent on the presence of VEGFR-1. Gabor Gabel (University of Dresden Hospital, Dresden, Germany) reported finding a noncoding SNP in the A20 gene that regulates TNF-α expression that may influence artherosclerotic risk.

The first afternoon session focused on aneurysms and was comoderated by April Boyd (SVS) and Alan Daugherty (AHA). Kathleen G Raman (Washington University, MO, USA), demonstrated involvement of the receptor for advanced glycation end-products (RAGE) in the pathogenesis of abdominal aortic aneurysms; she reported a threefold increase in RAGE expression in aneurysmal human tissue compared with unaffected aorta and the prevention of AAA formation in mice after the administration of RAGE blockade. John Curci (Washington University, WA, USA) described the enhanced aneurysmal degeneration in a smoke-exposed mouse model that was found to persist even in mice that were only previously exposed to tobacco smoke. This effect on AAA development was also transmissible to smoke-free animals with leukocyte preparations from smoke-exposed animals. Bo Liu (University of Wisconsin, WI, USA) discussed the contribution of PKCδ to the development of AAA through the regulation of MCP-1-mediated proinflammatory signaling. Castigliano M Bhamidipati representing a collaboration between the University of Virginia (VA, USA) and AstraZeneca, reported how the inhibition of 5-lipoxygenase can reduce aortic dilatation and preserve elastic lamina in an elastase model of AAA.

A series of focused presentations on stem cells and tissue engineering concluded the first day of VRIC programming, and was comoderated by Ravi Veeraswamy (SVS) and David Dichek (AHA). Laura Shankman (Gary Owens’ Laboratory at the University of Virginia), presented her work on the modulation of smooth muscle cells to a macrophage-like state in atherosclerosis. This exciting work suggests that smooth muscle cells, not monocytes, contribute a significant fraction of macrophage-like cells in atherosclerotic lesions and suggest novel therapeutic targets to stabilize plaques. Khanh P Nguyen (Conte Laboratory, University of California, CA, USA) discussed the regulation of vascular smooth muscle cell survival by Hsp–chaperone complexes and provide additional evidence for the cytoprotective effects of mitochondria. Laura E White (Methodist Hospital, TX, USA) showed that ischemic acute kidney injury results in pulmonary endothelial cell transcriptional activity distinct from that caused by uremia. Yanjie Qi (University of Rochester, NY, USA) presented work from the Gillespie laboratory implicating the TGF-β signaling pathway as being necessary for fibroblast activity in the setting of chronic venous insufficiency; fibroblasts were treated with stretch to simulate the in vivo environment of advanced lower extremity venous disease, and altered TGF-β signaling was discovered. This work suggests novel strategies that may be efficacious in the treatment of venous ulcerations. Zhao-Jun Liu (University of Miami, FL, USA) reviewed his work from the that implicates involvement of Notch signaling in atherosclerosis; this work was quite provocative but strongly based on both animal models as well as human data. Matthew J McHale (University of Texas Health Center, TX, USA), discussed how removal of sex hormones in male and female mice led to opposite effects on adipocyte accumulation after muscle injury, suggesting the importance of gender-specific treatments after muscle injury.

VRIC-ATVB combined sessions

Following last year’s model, VRIC programming was also present at the following day’s ATVB meeting, with several sessions planned and presented in conjunction with the ATVB program committee. In particular, an ATVB concurrent session was jointly sponsored by the SVS and AHA, and comoderated by VRIC chair Alan Dardik (SVS) and Gary Owens (AHA). The invited address by Gary Owens (University of Virginia, VA, USA), discussed his work on the phenotypic switching and modulation of smooth muscle cells. Notably, he has found that up to 35% of cells identified as macrophages in atherosclerotic plaques may be de-differentiated smooth muscle cells. This novel work provides both exciting new mechanisms of vascular pathology as well as potential new therapeutic targets. Mette K Hagensen (Aarhus University, Aarhus, The Netherlands) showed that circulating endothelial progenitor cells do not contribute to endothelial regeneration in her murine carotid injury model. Junji Moriya (Chiba University Graduate School of Medicine, Chiba, Japan) presented evidence that suggests that semaphorin, an axon guidance molecule, may be a novel target for therapeutic angiogenesis strategies. This session was very well attended and generated much discussion.

Several other sessions were planned jointly between the VRIC and ATVB program committees, including the concurrent session on vein graft biology. Christopher Owens (University of California San Francisco, CA, USA) gave the invited talk on inflammation and vein graft disease, focusing on his clinical work with human patients. Other talks included work from the Florida, UCSF, Nashville, Pittsburgh and Harvard groups. There was a large showing of both SVS and AHA members in the audience, and the discussion from this translational session was quite spirited.

Talks from the main VRIC session were also presented at the ATVB poster session for discussion between the surgical scientists and the cardiovascular researchers and physicians in the AHA. Feedback from this session reflected the excitement for the quality of the science presented at VRIC, as well as the formation of collaborations between attendees formerly seen as representing diverse disciplines but actually representing diverse expertise.

Conclusion

The integrated VRIC-ATVB meeting, which is currently in its third year, allows vascular surgeon–scientists to have their work discussed in the context of the larger vascular biology scientific community, rather than being viewed as isolated ‘surgical research’ without a home. Vascular surgeons and vascular biologists evaluate and discuss the surgical science, form collaborations and provide a much-needed venue for vascular surgery trainees to present their work. Building a positive feedback cycle, the quality of the vascular surgery scientific work continues to be included among the best of international vascular research. We look forward to next year’s VRIC meeting, to be held again in conjunction with ATVB, in Chicago, USA, 17–18 April 2012.

Acknowledgements

The following authors include the members of the 2010–2011 SVS Research and Education committee: April Boyd, Ankur Chandra, John Curci, Alan Dardik (Chair), Matthew Eagleton, Raul Guzman, Melina Kibbe, Gilbert Upchurch, Ravi Veeraswamy and Omaida Velazquez. The authors acknowledge and sincerely appreciate the help of Robert Hegele, Murray Huff and Steven Lentz of the AHA in their unrelenting efforts to produce the coordinated VRIC-ATVB meeting. We acknowledge and greatly appreciate the help of Victora Fahey, Sarah Murphy and Julie Green.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.