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In Memoriam: Paul M. Vanhoutte

2019; Wiley; Volume: 597; Issue: 24 Linguagem: Inglês

10.1113/jp279124

1469-7793

Matthias Barton, Carmine Cardillo,

Heart Rate Variability and Autonomic Control

Now cracks a noble heart. Good night, sweet prince, And flights of angels sing thee to thy rest! On 23 August 2019, science lost one of its great minds: Paul Michel Georges Remi Vanhoutte, born on 26 November 1940 in Merelbeke near Ghent in Belgium, unexpectedly died in Paris after he had suffered a fall 10 days earlier. He was 'one of the fathers of vascular biology' (Heistad, 2008) who contributed to and shaped our understanding of how vascular endothelial cells regulate blood flow under physiological conditions and in disease. Dr Vanhoutte, or Paul (as he asked everybody to call him, regardless of age or position), was born at the time of the German occupation of his country during World War II and grew up in a family with several siblings. He attended a Jesuit school, developing a keen interest in humanities and classics, before becoming a Candidate in Natural Sciences in 1961 (equivalent to BS) and a Doctor in Medicine, Surgery and Obstetrics in 1965 (equivalent to MD) at the University of Ghent. After completing a Licentiate in Physical Education (equivalent to MS) in 1970 in Ghent, Dr Vanhoutte obtained the Aggregatie Hoger Onderwijs (Aggregation in Higher Education, equivalent fo habilitation/PhD degree) at the University of Antwerp in 1973. Dr Vanhoutte discovered his passion for science early, a love affair that would last more than half a century until his untimely death. From 1961, as third year medical student, he worked as student-assistant in the laboratory of physiologist Dr Isidor Roger Leusen (1923–2010) in Ghent studying venous reactivity and cardiovascular adaptation to exercise, and continued to work with him after graduating until 1968. Genuine curiosity certainly was one of Dr Vanhoutte's most significant traits; many of his groundbreaking discoveries initially challenged but subsequently revolutionized the understanding of the regulation of blood flow and the way that diseases affect cardiovascular function. Dr Vanhoutte was instrumental in shaping our view that endothelial cells are much more than a simple inner lining of arterial and venous blood vessels. Dr Vanhoutte's decision early in his career to follow his calling for science and knowledge (Wetenschap, the Flemish word for science, literally means 'knowledge creation') was his gift to medicine and science equally, as well as to those who had the chance to learn from and work with him. He called those who trained with him as his 'scientific children', those who trained with his pupils, his 'scientific grandchildren', and those, who trained with his scientific grandchildren his 'scientific great-grandchildren' (Vanhoutte, 2010). Indeed, science was Dr Vanhoutte's second family and his intellectual home. It was impossible to separate him from what he loved, and he showed the way to several generations of young scientists who continued the way that Dr Vanhoutte and others had started. Following postdoctoral studies in Ghent with Dr Leusen, Dr Vanhoutte in 1968 moved to the Mayo Clinic in Rochester, MN, USA, working under the mentorship of Irish-born physiologist Dr John T. Shepherd (1919–2011) (Vanhoutte & Shepherd, 1969; Joyner, 2011; Vanhoutte et al. 2012). After returning to Ghent in 1969, he accepted a position as Assistant Professor at the Mayo Clinic in 1972 (Fig. 1). In 1973, he moved again back to Belgium to become Head of the Laboratory of Physiopathology at the Department of Medicine to the University of Antwerp where he was promoted to Professor of Pharmacology and Physiology in 1975. Already at that time, Dr Vanhoutte had developed an interest in the relaxation of blood vessels: intrigued by observations published in 1962 by Dr Roger Jelliffe (born 1929) (Jelliffe, 1962; Barton, 2011), Dr Vanhoutte began his own investigations, in 1971, of the mechanisms underlying the relaxing effect of ACh on the vascular wall (Vanhoutte & Shepherd, 1973; Vanhoutte, 1974). In the spring of 1977, together with his mentor Leusen, Dr Vanhoutte organized a meeting in Wilrijk, Antwerp, entitled 'Mechanisms of Vasodilatation' (MOVD) as a satellite symposium to the 27th International Congress of Physiological Sciences in Paris (Vanhoutte & Leusen, 1978) – one year before Dr Robert F. Furchgott (1916-2009) began to study the mechanisms of ACh-induced vasodilatation after an accidental finding made in May 1978 as a result of an error made by a technician (Furchgott, 1983). In the same year, expanding on his initial observations that ACh induces relaxation (Vanhoutte, 1974), Dr Vanhoutte and Jo De Mey reported that relaxation to ACh was oxygen-dependent (De Mey & Vanhoutte, 1978), which later would be shown to be the case for the enzymes producing nitrogen monoxide (or nitric oxide, NO), the NO synthases (Vanhoutte et al. 2016). At the Fall Meeting of the American Society of Pharmacology and Therapeutics (ASPET), held 17–21 August 1980 at the Mayo Clinic in Rochester, both Dr Vanhoutte and Dr Furchgott independently presented abstracts reporting endothelium-dependent relaxation of arterial blood vessels (De Mey & Vanhoutte, 1980; Furchgott & Zawadzki, 1980a) when Dr Furchgott had just submitted a manuscript to Nature (Furchgott & Zawadzki, 1980b). More than 1 month before Dr Furchgott's article appeared in print, Dr Vanhoutte and Dr. Jo De Mey had submitted their manuscript to the Journal of Physiology. However, the review process took time and the paper was not published until July 1981 (Fig. 2) (De Mey & Vanhoutte, 1981). Despite the fact that they both had been involved in the discovery of endothelium-dependent relaxation, Dr Vanhoutte always credited Dr Furchgott, reflecting both his humility and his admiration for Dr Furchgott, who had become a close friend (Furchgott & Vanhoutte, 1989; Vanhoutte, 2009b, 2010). Dr Vanhoutte again returned to the Mayo Clinic in 1981 as Professor of Physiology and Pharmacology. The years in Antwerp and in Rochester became the most fruitful in Dr Vanhoutte's career. He discovered that, in addition to its vasorelaxant properties, endothelium also mediates vasoconstrictor effects, given that removal of endothelium decreases the contractile effect of anoxia in both arteries and veins; Dr Vanhoutte and Dr De Mey (who began working with Dr Vanhoutte as a master's student on August 26, 1976 at 4:30 pm) reported their findings in manuscripts submitted in 1981 (Fig. 2) (De Mey & Vanhoutte, 1983) and in 1982 (De Mey & Vanhoutte, 1982; Barton, 2011). Subsequent studies in his and other laboratories eventually led to the identification of a number of endothelium-derived vasoconstrictor agents, including thromboxane A2 and other arachidonic acid-derived prostanoids, superoxide anions and endothelin (Hickey et al. 1985; Rubanyi & Vanhoutte, 1985, 1986; Yanagisawa et al. 1988; Vanhoutte & Tang, 2008; Rubanyi, 2011; Vanhoutte, 2011; Vanhoutte, 2013a; De Mey & Vanhoutte, 2014). In this regard, in his lecture on May 21 at the MOVD/EDH 2019 Symposium held last May in Rotterdam entitled 'NO, from good to bad', a title he coincidentally chose for one of his last papers (Vanhoutte, 2018) that sadly turned out to be his swan song, he hinted that enhanced vascular contraction following hypoxia also involves endothelial NO, which, instead of being a vasodilator acting via soluble guanylyl cyclase to produce guanosine-3',5'-cyclic monophosphate (cGMP), becomes a vasoconstrictor by stimulating biased activity of the enzyme, resulting in the generation of inosin-3'-5' monophosphate (cIMP) (Vanhoutte et al. 2016; Vanhoutte, 2018). Finally, together with Dr Michel Feletou, Dr Vanhoutte first demonstrated that factors different from NO are involved in endothelium-dependent vasorelaxation, in a manuscript that he submitted in April 1987, by showing that NO-independent endothelium-dependent relaxation can be mediated by hyperpolarization of vascular smooth muscle cells (Feletou & Vanhoutte, 1988). A number of endothelium-derived hyperpolarizing factors have subsequently been identified, including cytochrome P450 metabolites, epoxyeicosatrienoic acids, potassium, H2O2, and endothelial gap junctions (Garland et al. 2011; Feletou & Vanhoutte, 2017). The figure legends below are those used by Drs De Mey and Vanhoutte in the original publications. The data shown on the left, showing endothelium-dependent relaxation, were submitted for publication in October 1980 (De Mey & Vanhoutte, 1981) and those on the right, showing endothelium-dependent contraction, in December 1981 (De Mey & Vanhoutte, 1983) Left: Inset: isometric tension recording in an isolated canine femoral artery with endothelium intact. Effect of ACh during response to exogenous adrenaline. Graph: comparison of the relaxing properties of increasing concentrations of ACh in paired rings of the same arteries (n = 6) with (●) or without (○) endothelium. The relaxations are expressed as percent depression after control response to 10−7 m noradrenaline (mean increase in tension, respectively) and shown as means ± S.E. means. Right: Representative experiment showing the effect of incubation and glucose-free solution on the response to 10−7 m noradrenaline (NA) with superimposed anoxia (N2) and rings with (A) and without (B) endothelium from the same canine femoral artery. In 1989, Dr Vanhoutte moved to the Baylor College of Medicine in Houston, TX, USA, as Professor of Medicine, Pharmacology and Physiology and Director of the Centre for Experimental Therapeutics. He returned to Europe in 1992, accepting a position as Vice-President Research and Development at the Institut de Recherches Internationales Servier in Paris, France, the city that he made his home for the rest of his life (Fig. 3). His energy and passion for his work induced him to escape a compulsory retirement in 2002, and so, in 2003, he moved to the University of Hong Kong as Distinguished Visiting Professor and Director of the Biopharmaceutical Development Centre. In 2006, he became the Head of the Department of Pharmacology and Pharmacy at the University of Hong Kong and, from 2015, he was permanent Visiting Professor at the same institution. Concurrently, he held multiple adjunct or visiting appointments at universities in many countries, including Australia, Canada, China, Denmark, Korea, Switzerland and the USA in an endless effort to inspire and supervise PhD students and advising senior investigators, 'do not repeat my mistakes', as he often stated. 'It comes in bits and pieces. You never got the full answer, you get a partial answer. And each partial answer asks several new questions, and then you perk along and you get there. And once in a while you get something that really is exciting. Not all the time, but you know, it's more frequent than one thinks. The most important thing, you know, is: luck is very important, but everybody is lucky in research. Most people don't recognize their luck. So you have to focus – you cannot spread yourself too thin – but it is the unexpected that will give you the gold. If [someone] tells you 'I want you to test this hypothesis, because I expect this to happen' – and it doesn't happen, that's the jackpot! When something different happens than we project or expect!' The immense contribution of Dr Vanhoutte to the progression of scientific knowledge relies fundamentally on his studies demonstrating how endothelial cell-derived substances may not only interfere with, but also contribute to the development of atherosclerosis and cardiovascular disease (Vanhoutte et al. 2017). A journal's scientific credibility and reputation, not its citation metrics, were essential for Dr Vanhoutte when deciding where to send his manuscripts. He chose to publish his most significant discoveries in the Journal of Physiology, the world's oldest physiology journal in existence, as established in 1876 shortly after the founding of the Physiological Society in London. Dr Vanhoutte was a long-standing member of the Physiological Society, and became an Honorary Member in 2006. The Editors of the Journal of Physiology have kindly agreed to publish a Commemorative Issue comprising Dr Vanhoutte's contributions published in the Journal between 1975 and 2008 coinciding with the publication of this obituary (Barrett, 2019). This Commemorative Issue of the Journal of Physiology on Dr Vanhoutte will establish a permanent memorial highlighting and commemorating his major achievements that stand out among his enormous impact on science, with a legacy of more than 1000 published scientific articles. 'In early 1985 the author's laboratory reported that under superfusion-bioassay conditions superoxide anions were scavenging EDRF. After a long battle with reviewers and editors, the full description of these observations finally was published at the same time as a similar conclusion [was] reached by Salvador Moncada and colleagues.' Dr Vanhoutte, like Nobel laureate Sir John R. Vane (Howlett, 1998), personally proposed Dr Furchgott for the Nobel Prize (Vanhoutte, 2010). However, although Dr Vanhoutte had been nominated for the Nobel Prize himself, he never received it. He once jokingly mentioned that he was happy about not being among its recipients because otherwise he might not have continued science (Vanhoutte, 2010). Dr Vanhoutte's immense knowledge and ability to serve as an advocate for science was widely recognized: he chaired the International Union of Basic and Clinical Pharmacology (IUPHAR) Committee for Receptor Nomenclature from 1989 to 1998 (Vanhoutte & Spedding, 1995; Vanhoutte et al. 1996) and was Secretary General of IUPHAR from 1998 to 2002, as well as its President from 2002 to 2006. For almost 20 years (1989 to 2007), Dr Vanhoutte served as Editor-in-Chief of the Journal of Cardiovascular Pharmacology, and as an Associate Editor or Editorial Board Member of many renowned journals in the field. He was an Honorary Fellow of the British Pharmacological Society, as well as an Honorary Member of the Collège Français de Pathologie Vasculaire, the Société Française de Cardiologie, the Academia Nacional de Medicina do Brasil, the Chinese Pharmacological Society and the Deutsche Gesellschaft für Angiologie. Other distinctions included memberships and fellowships of the Academia Europaea, L'Académie nationale de Pharmacie (Paris), the Académie Royale de Médecine de Belgique, the American College of Cardiology and the American Heart Association. In recognition of his achievements, Dr Vanhoutte was awarded the Gold Medal of the City of Paris (1986), the Carl J. Wiggers Award of the American Society of Physiology (2006), the Novartis Award for Hypertension Research of the Council for High Blood Pressure Research of the American Heart Association (2010) and the 'Officer of the Crown' order, one of its highest honors of the Kingdom of Belgium (2006). 'It's not the technology you use, but the question you ask and how you answer it!' 'The only way to be successful is to surround yourself with people who are younger and more intelligent than you. And let them grow, let them "get"! Just give them the kind of atmosphere they need to grow and bloom! […] If you're talking to young people and trying to help them and get excited about what they do, then you forget that you are a dinosaur!' 'Remember: It is not important to be first. It is important to be right!' 'It's a rough life, you know. Many hurdles and many disappointments. Whenever you get to the point that things work out and you understand something that you didn't understand before – then you get this feeling of achievement that no money in the world can buy. And money can't buy everything. It cannot buy the joy that we get from our work! I started research […] more than fifty years ago but as of today I am still as intrigued, as interested as the first day, and I think that only research can give you that. So will a bit of luck, well, a lot of luck, you will get that, too!' Dr Vanhoutte (Fig. 5) leaves such a great legacy to his field that to report it all in a brief tribute is an impossible task. The Paul M. Vanhoutte Commemorative Issue of the Journal of Physiology, however, summarizes and preserves some of his greatest achievements (Barrett, 2019). We appreciate how privileged we have been for the opportunity to have met and spent time with this great scientist and delightful human being. We truly believe that getting to know him, as a man who was humble, of great sensitivity, kind-hearted and friendly, has added an unforgettable personal dimension to the interaction with a giant of science. Our thoughts are with Dr Vanhoutte's wife of 53 years, Jacqueline, as well as his children and his family. Paul Vanhoutte lives on in the hearts of those who knew him and his legacy will inspire generations of scientists to come. The authors are indebted to Dr Jo De Mey for critical reading of the manuscript and for his valuable comments and to Madame Jacqueline Vanhoutte for the photograph of her late husband.