Abstract
Professor Kari Alitalo delivered the keynote address, in which he presented the role of hypoxia in angiogenesis by activation of the complex vascular endothelial growth factors (VEGF) pathways and the consequences of this activation in cardiovascular development and lymphangiogenesis. The seminar provided many insights into specific subjects to be further discussed at the meeting, including oxygen sensing, the role of hypoxia in metabolism, cancer, angiogenesis, and the potential clinical effect of specific PHD inhibitors on various hypoxia-mediated pathways. Appropriately, the first day began with oxygen sensing, starting off with comparative aspects and moving on to focus on mammalian mechanisms, as the majority of attendees research mammalian responses to hypoxia. Unpublished data were included in most talks, revealing important advances in the understanding of the control of hypoxia-inducible transcription factors 1 and 2 (HIF1, HIF2), mechanisms allowing HIFs to have discrete and distinct actions, temporal differences in the molecular response to hypoxia, and the role of mitochondria in oxygen sensing. These topics led naturally into the sessions on hypoxia and metabolism, in which new data on hypoxia's role in metabolism in a variety of pathologies, including obesity, renal cancer, and pulmonary fibrosis, were presented. The final session of the day delivered exciting new data revealing greater potential for discrete control of HIF(s) activation that may be exploited in therapeutic strategies, including specificity of PHDs, HIF phosphorylation, and reactive oxygen species. This session stimulated keen interest in the workshop on PHD-inhibiting drugs held later in the meeting.
The second day began with sessions focusing on the role of hypoxia in disease, including skeletal muscle injury, central nervous system injury, including a fascinating new in vitro, three-dimensional, multicellular model of the blood–brain barrier, and hypoxic activation of the lymphocytic choriomeningitis virus (LCMV), which has significant implications for kidney transplants and frequent miscarriage. A fascinating set of data were presented in which the sensitivity and mechanisms of HIF2 activation and subsequent erythropoietin (EPO) production were implicated in the development of renal clear cell carcinoma. This led to a session on EPO, EPO receptor (EPOR), and erythrocytosis. The genetic origins of erythrocytosis in human disease revealed mutations in Von Hippel–Lindau (VHL), PHD2, and HIF2A genes, and various laboratory-induced mutations in EPOR revealed that the location of EPOR (cell membrane or cytosolic) can be manipulated during hypoxia, that GATA4 is instrumental in EPOR transcription in the heart, and that CITED2 is crucial for mediating hematopoietic stem cell fates during hypoxia.
The seminar series continued on the third day beginning with the effects of high altitude on exercise performance. This began with a novel seminar title, a quote adapted from one of the most famous early hypoxia–altitude researchers, Peruvian Carlos Monge: “Humans are a sea level design.” The role of erythrocytosis and the adaptation of human populations to high altitude were explored with new data suggesting that manipulation of iron concentrations may alter human response to chronic hypoxia. This was followed by the presentation of invasive and unique human studies that expanded on the hypothesis that iron stores may contribute to successful or failed adaptation to chronic hypoxia. In the following session on lymphangiogenesis and hypoxia, world-class investigators presented unpublished data implying that HIF1 and HIF2 have opposite effects on nitric oxide production, thus altering vascular response to hypoxia; hypoxic induction of hemeoxygenase 1 (HO1) mediates angiogenesis and proliferation during hypoxia, thus mediating metastasis; and the hypoxia—VEGF—matrix metalloproteinase (MMP9) pathway may mediate blood–brain barrier permeability during hypoxia.
An afternoon session was dedicated to short presentations by junior investigators and graduate students that further highlighted the ongoing research in numerous areas of hypoxia science and the role of the younger generation in hypoxic research. Daily poster sessions provided another platform for the presentation of novel complementary data, in addition to that presented in seminars. There was lively discussion and high attendance at these sessions, which generated considerable opportunities for collaboration between laboratories throughout Europe and the world.
Further activities included a training school and workshop that provided novel forums for a number of topics. The training school focused on hypoxic cell culture and included presentations by both academic and commercial scientists. It began with a very focused review by Roland Wenger on the gas laws and the importance of fully understanding and considering the physics of these principles when designing experiments using hypoxic cell culture. This was followed by presentations from scientists representing companies that make hypoxic cell culture hoods and oxygen- monitoring devices; they shared valuable information about important considerations when selecting and using equipment specialized for hypoxic cell culture. Their experience with a large variety of research needs gave participants new and critical insights into various aspects of hypoxic cell culture that are often ignored or overlooked. The knowledge gained from this training school will invariably improve the quality of experiments performed by participants and their colleagues, thus greatly improving the quality of the data resulting from these numerous international laboratories and significantly enhancing the field of hypoxia biomedical research. The companies and sponsors contributing to this endeavor were impressed with the attendance at these sessions and the interest in their presentations. This resulted in a strong interest in supporting such conferences in the future.
The workshop focused on PHD-inhibiting drugs and was held as a discussion forum. Initial presentations by academic and commercial scientists were followed by a round-table discussion on how to best forge links between the academic and pharmaceutical industry. The consensus at the conclusion of this workshop was that it is not only groundbreaking discoveries that provide great insight for the pharmaceutical industry to expand on, with the goal of developing better and more specific PHD inhibitors. Further, pharmaceutical companies would like to forge closer ties with all academic researchers, not just senior scientists, as they believe that very important basic science data are coming from their laboratories. There was general agreement that such workshops would be highly attended at other meetings if they were available. The overall primary consensus was that academic and industrial scientists alike are united in their desire to create a product useful for hypoxia-oriented research and medicine.
Overall, this research conference provided an excellent opportunity for scientists from a number of diverse fields, including cancer, immune disorders, inflammation, pulmonary disorders, adaptation to high altitude, fetal development, and cardiovascular disease, to interact and present data on a very focused and critical part of their research: hypoxia. Speakers revealed an unprecedented amount of unpublished data, creating riveting presentations. The additional and novel opportunity to interact closely with industrial scientists in the training school and workshop allowed, for the first time, the chance for both groups to hear from each other in a forum inviting discussion and learning in an open and low-pressure environment. It is certain that many future new investigations and collaborations will develop from this impressive event.