Research Report 2010 - MDC

Left panel: in vivo imaging of blood vesselsand organ development in transgeniczebrafish expressing GFP in developingblood vessels. Right panel: detail ofdeveloping hepatic vasculature.(Klein&LeNoble, 2009, unpublished)Mechanosensing, Arteriogenesis and IschemicDiseasesArteriogenesis, the outward remodeling of pre-existingsmall collateral arterial networks, occurs as a responseto vascular occlusion or stenosis and importantly determinesthe clinical outcome of ischemic cardiovasculardisease. Release of vasodilators and activation ofinflammatory pathways allowing influx of monocytesmay result in revascularization and restoration of bloodflow into the hypoperfused ischemic area. Therapeuticarteriogenesis is considered of major clinical importanceto treat the increasing population with complexocclusive artery diseases. Distinct differences existbetween animal strains and patients with regard to collateraldevelopment and response to angiogenicgrowth factors. We aim at understanding the molecularmechanism accounting for such differences. In particularwe focus on the formation of native collateralsand efficiency of collateral recruitment and maintenance.Hemodynamic forces exerted by flowing bloodand neural guidance molecules play a critical role in initiationand maintenance of the arteriogenesisresponse. We are interested in how biophysical signalsexerted by flowing blood activate specific genetic programsessential for arterial differentiation. The role ofneural guidance molecules in arteriogenesis is studiedin conditional mutant mice exposed to ischemic vascularstress (femoral artery occlusion, cardiac infarct,stroke models). We examined adaptive recovery fromsuch pathological insults using laser-doppler flow, perfusion-microspheres,imaging including standardangiography, MRI and micro CT. In addition, we performedextensive molecular and histological analysis oftarget organs. Based on a comprehensive analysis ofhemodynamic parameters in experimental models, andin vitro analysis we identified a specific component ofthe shear stress signal relevant for induction of arterialmarker genes and arteriogenesis. At present we arecharacterizing the promoter elements triggered byshear stress relevant for arterial mechanosensing. Ourdata furthermore show that in mice native collateralsare already present at time of birth, but are progressivelypruned during the course of postnatal life. Both thecollateral numbers at birth, as well as their maintenance,are influenced by neural guidance gene function.The outstanding question is to what extent neuralguidance gene function may account for the differencesbetween “good” and “bad” collateralizationresponses as observed in clinical practice. In collaborationwith clinical research partners we are evaluatingnovel strategies and compounds to stimulate arteriogenesisin patients suffering from vascular occlusivedisease. In this context we now provided the proof ofconcept that, in humans suffering for ischemic heartdisease, stimulation of shear stress using non-invasiveexternal counter pulsation therapy, improves functionalrevascularization towards the ischemic regions.Selected PublicationsBuschmann EE, Utz W, Pagonas N, Schulz-Menger J, Busjahn A, Monti J,Maerz W, le Noble F, Thierfelder L, Dietz R, Klauss V, Gross M, BuschmannIR; On behalf of the Arteriogenesis Network (2009). Improvement offractional flow reserve and collateral flow by treatment with externalcounterpulsation. Eur J Clin Invest. 2009 Jul 2. [Epub ahead of print]Tintu A, Rouwet E, Verlohren S, Brinkmann J, Ahmad S, Crispi F, van BilsenM, Carmeliet P, Staff AC, Tjwa M, Cetin I, Gratacos E, Hernandez-AndradeE, Hofstra L, Jacobs M, Lamers WH, Morano I, Safak E, Ahmed A, le Noble F(2009). Hypoxia induces dilated cardiomyopathy in the chick embryo:mechanism, intervention, and long-term consequences. PLoS One. 2009;4(4): e5155.Buschmann IR, Lehmann K, Le Noble F (2008). Physics meets molecules: ismodulation of shear stress the link to vascular prevention? Circ Res.102(5): 510-2.Suchting S, Freitas C, le Noble F, Benedito R, Bréant C, Duarte A, EichmannA (2007). The Notch ligand Delta-like 4 negatively regulates endothelialtip cell formation and vessel branching. Proc Natl Acad Sci U S A. 104(9):3225-30.Lu X*, Le Noble F*, Yuan L*, Jiang Q, De Lafarge B, Sugiyama D, Bréant C,Claes F, De Smet F, Thomas JL, Autiero M, Carmeliet P, Tessier-Lavigne M,Eichmann A (2004). The netrin receptor UNC5B mediates guidanceevents controlling morphogenesis of the vascular system. Nature432(7014): 179-86. *equal contributionCardiovascular and Metabolic Disease Research 21