My main interest in science since 40 years was (and still is) the capacity of the vascular system to repair itself. In particular its ability to build a new artery in cases of arterial occlusion. When I started my post-doctoral training in pathology more than 40 years ago, I made the observation that patients dying from non-cardiac causes exhibited, upon autopsy, occluded coronary arteries but no infarctions. These hearts   had developed a natural “bypass” circulation that had salvaged their myocardium. This was not a frequent observation but I found that often enough to come to the conclusion that a genetic program must exist that enabled the heart to use this escape hatch when needed. I brought this observation to the laboratory and found that indeed mammals differed in their ability to develop a collateral circulation and that man was not at the bottom of the evolutionary scale for its ability to build one. I could show that the collateral arteries were the product of active cell proliferation and not one of passive stretch. Already in the late 1960ies I could show that endothelial and smooth muscle cells of these tiny pre-existent arterioles synthesized DNA and underwent cell division whereupon the collateral vessel diameter increased manyfold reaching thereby full arterial size. In 1975 I discovered together with Dr. Jutta Schaper that circulating monocytes attached to the wall of developing canine coronary arterioles and later studies revealed that these cells are indeed essential to the growth of collateral arteries, because removal of monocytes or tampering with their activity inhibited arterial growth. We discovered that monocyte chemo-attractant factor (MCP-1) is important for the repair and genetic targeting of this factor as well knock- out of its cognate receptor (CXCR2) inhibits arteriogenesis. These studies were the experimental basis for the subsequent clinical studies with bone marrow derived stem cells that are now intensely studied. We also found that the physical force that triggers collateral artery growth is the fluid shear stress and we designed new experiments to alter and maximally increase fluid shear stress. Arterial tissue from these experiments was subjected to genome-wide screening for differentially expressed genes and we discovered an abundance of new and unsuspected genes that we are currently studying. We found that several signaling pathways are involved in arteriogenesis namely the MAPKinases ERK-1, 2, the Rho- and the NO-pathway. Our studies led to the new concept of “Arteriogenesis”, the adaptive growth of collateral arteries, which differs from angiogenesis because it does not rely on ischemia/hypoxia and its growth factor needs differ significantly from that of capillary sprouting. Our studies have advanced far enough to begin thinking of ways and means to translate our knowledge, accumulated over 4 decades, into strategies for new pharmacological agents. Should this be possible the dream of my life would come true.

Dear Naranjan, you may not remember that your advice was once very helpful to me. We met 25 years ago at Duke University where you had given a seminar at Bob Jennings lab. I had taken you out to dinner and I told you the reason for spending a sabbatical year in Bob’s Department: I had felt, that my research with the collateral circulation had got stuck and was searching for a different topic. You strongly advised me not to do that but stick to the topic for which was already well known. I heeded your advice and with the new molecular methods my research in collaterals took a new and productive turn. Thanks very much again for your serendipitous advice.