In Memoriam: Paul M. Vanhoutte

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 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 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 Furchgott 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 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 Yanagisawa et al. 1988; Vanhoutte Rubanyi, 2011; Vanhoutte, 2011; Vanhoutte, 2013a; De Mey 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 Feletou 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.