Correspondence Response to Letter Regarding Article, “Vitamin D Promotes Vascular Regeneration” We thank Dr Kain for her interest in our work.1 Her letter puts our study into a larger population-based perspective and raises the general issue of whether vitamin D3 deficiency should be prevented by dietary supplementation or sunlight exposure. We agree with her statement that moderate sunlight exposure is probably not harmful. That avoiding sunlight is associated with increased mortality, however, is only a coincidental finding of unclear causality. Obviously, mood, mobility, physical activity, and other factors affect this association. We agree with Dr Kain’s statement that outdoor physical activity particularly exerts protective effects on the cardiovascular system at large, which extend far beyond the increased production of vitamin D. Nevertheless, we feel that advising patients to undertake lifestyle changes may not be sufficient to correct vitamin D deficiency. Not only is sunlight intensity in the cooler regions of our planet low during wintertime, but clothing further limits sun exposure. Even in summertime, ultraviolet irradiation does not raise vitamin D levels reliably.2,3 Furthermore, daily work rhythms force many people (including physicians and scientists) to practice outdoor activities in the late hours of the day with less ultraviolet radiation. In addition, people with limited mobility do not receive sufficient solar light exposure. Importantly and relevant to Dr Kain’s letter, people with higher levels of skin pigmentation (like southern Indians) are particularly prone to experience low vitamin D levels with higher requirements for vitamin D supplementation, especially after migration.4 Dr Kain wonders what the impact of physical activity on the active vitamin D hormone (1,25-dihydroxy vitamin D3) could be because production and degradation of the hormone are controlled by inducible enzymes. Indeed, expression of 24-hydroxylase not only is a measure of active vitamin D hormone abundance but also is responsible for hormone degradation. In fact, we also observed a great induction of 24-hydroxylase in response to vitamin D supplementation in the clinical part of our work. To the best of our knowledge, it is not known whether 24-hydroxylase expression is regulated by physical exercise. It is at least noteworthy that exercise induces mitochondrial genes and that the 24-hydroxylase resides in this compartment. Moreover, athletes are not protected from vitamin D deficiency.5 Skeletal muscle cells express enzymes involved in vitamin D activation, but their contribution to total body vitamin activation (compared with that of the kidney) appears minor. More clinical studies, as suggested by Dr Kain, are therefore needed to better define the interplay of vitamin D and exercise.

Disclosures None. Michael Sze Ka Wong, PhD Institute for Cardiovascular Physiology Goethe-University Frankfurt, Germany Matthias S. Leisegang, PhD Christoph Kruse, MSc Institute for Cardiovascular Physiology Goethe-University Frankfurt, Germany German Center for Cardiovascular Research Partner Site RheinMain Frankfurt, Germany Juri Vogel, MSc Institute for Cardiovascular Physiology Goethe-University Frankfurt, Germany

Christoph Schürmann, PhD Institute for Cardiovascular Physiology Goethe-University Frankfurt, Germany German Center for Cardiovascular Research Partner Site RheinMain Frankfurt, Germany Nathalie Dehne, PhD Andreas Weigert, PhD Institute for Pathobiochemistry Goethe-University Frankfurt, Germany Eva Herrmann, PhD Institute for Biostatistics and Mathematical Modeling Goethe-University Frankfurt, Germany German Center for Cardiovascular Research Partner Site RheinMain Frankfurt, Germany Bernhard Brüne, PhD Institute for Pathobiochemistry Goethe-University Frankfurt, Germany Ajay M. Shah, MD, PhD Cardiovascular Division King’s College London BHF Center of Excellence London, UK Dieter Steinhilber, PhD Institute of Pharmaceutical Chemistry/ZAFES Goethe-University Frankfurt Frankfurt am Main, Germany Stefan Offermanns, MD Department of Pharmacology Max Planck Institute for Heart and Lung Research Bad Nauheim, Germany German Center for Cardiovascular Research Partner Site RheinMain Frankfurt, Germany Geert Carmeliet, MD, PhD Clinical and Experimental Endocrinology KU Leuven Leuven, Belgium Klaus Badenhoop, MD Department of Endocrinology and Diabetes Internal Medicine 1 University Hospital Frankfurt Frankfurt, Germany Katrin Schröder, PhD Ralf P. Brandes, MD Institute for Cardiovascular Physiology Goethe-University Frankfurt, Germany German Center for Cardiovascular Research Partner Site RheinMain Frankfurt, Germany

(Circulation. 2015;131:e515-e516. DOI: 10.1161/CIRCULATIONAHA.114.014781.) © 2015 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.114.014781

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References 1. Wong MS, Leisegang MS, Kruse C, Vogel J, Schürmann C, Dehne N, Weigert A, Herrmann E, Brüne B, Shah AM, Steinhilber D, Offermanns S, Carmeliet G, Badenhoop K, Schröder K, Brandes RP. Vitamin D promotes vascular regeneration. Circulation. 2014;130:976–986. doi: 10.1161/CIRCULATIONAHA.114.010650. 2. Reusch J, Ackermann H, Badenhoop K. Cyclic changes of vitamin D and PTH are primarily regulated by solar radiation: 5-year analysis of a German (50 degrees N) population. Horm Metab Res. 2009;41:402–407. doi: 10.1055/s-0028-1128131.

3. Langer J, Penna-Martinez M, Wallasch M, Bon D, Badenhoop K. Time trend of UVB irradiation and the vitamin D concentration in German type 1 diabetes patients. J Steroid Biochem Mol Biol. 2013;136:218–220. doi: 10.1016/j.jsbmb.2012.11.008. 4. Guo S, Gies P, King K, Lucas RM. Sun exposure and vitamin D status as Northeast Asian migrants become acculturated to life in Australia. Photochem Photobiol. 2014;90:1455–1461. doi: 10.1111/ php.12349. 5. Owens DJ, Fraser WD, Close GL. Vitamin D and the athlete: emerging insights. Eur J Sport Sci. 2015;15:73–84.

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Response to Letter Regarding Article, ''Vitamin D Promotes Vascular Regeneration'' Michael Sze Ka Wong, Matthias S. Leisegang, Christoph Kruse, Juri Vogel, Christoph Schürmann, Nathalie Dehne, Andreas Weigert, Eva Herrmann, Bernhard Brüne, Ajay M. Shah, Dieter Steinhilber, Stefan Offermanns, Geert Carmeliet, Klaus Badenhoop, Katrin Schröder and Ralf P. Brandes Circulation. 2015;131:e515-e516 doi: 10.1161/CIRCULATIONAHA.114.014781 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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