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1. Origins of heterogeneity in tissueperfusion and metabolism
Project leader: Axel R. Pries
Coworkers: Bettina Reglin
Collaborators: Timothy W. Secomb, University of Arizona
In the heart and other tissues, perfusion and metabolic activity exhibit significant, spatially correlated heterogeneities. The causes for this functionally relevant heterogeneity are not known. The main question: Is flow adapted to heterogeneity in demand or does heterogeneity in demand result from flow heterogeneity?
Observed flow heterogeneity is mainly caused by unavoidable angioarchitectural heterogeneity of terminal vascular beds.
Approach: mathematical simulation combined with experimentally observed microvascular network structures. Simulations show that inherent geometric heterogeneites of vascular networks cause a heterogeneity of blood flow and PO2 which cannot be eliminated by sensitizing metabolic diameter adaptation. Adaptation of oxygen demand to differences in oxygen availability causes increased oxygen extraction, implying improved functional capacity. Thus, the main mechanism generating heterogeneous perfusion seems to be the inevitable structural heterogeneity of terminal vascular beds which cannot be fully compensated by structural adaptation of vessel diameters.
Figure: Schematic representation of mechanisms leading to heterogeneity of flow and oxygen levels. Arrows with blunt ends represent negative effects. Vascular networks inevitably exhibit substantial heterogeneity in topology and segment length due to the stochastic processes involved in angiogenesis and the 'dimensional problem. The resulting heterogeneity in oxygen levels may be reduced by adaptation of vessel diameters to metabolic signals (blue) or increased by local adaptation of oxygen demand to oxygen availability (red)
2. Heterogeneity of tumor microvascular networks: result of defective vascular adaptation?
Project leader: Axel R. Pries
Coworkers : Bettina Reglin, Michael Höpfner, Marlene Hinkeldey
Collaborators: Timothy W. Secomb, University of Arizona; Annemiek Cornelissen, Université Paris-Diderot, Paris, France
Tumor microcirculation exhibits high structural and functional heterogeneity leading to hypoxic regions and impairing treatment efficacy. Identification of respective causes may suggest new treatment approaches. Hypothesis: Abnormal adaptive responses to local hemodynamic and metabolic stimuli contribute to aberrant morphological and hemodynamic characteristics of tumor microcirculation. Normal mesenteric and tumor vascular networks were recorded by intravital microscopy. Computer models were used to estimate hemodynamics and oxygen distribution and to simulate vascular diameter adaptation in response to hemodynamic, metabolic and conducted stimuli. The assumed sensitivity to hemodynamic and conducted signals, the vascular growth tendency, and a random variability of vascular responses were altered to simulate 'normal' and 'tumor' adaptation modes. Properties of vascular networks were characterized by diameter mismatch at vascular branch points (d3var) and deficit of oxygen delivery relative to demand (O2 def). d3var and O2 def in the tumor (0.404 and 0.182) were higher than in normal networks (0.278 and 0.099). Simulated remodeling of the tumor network with 'normal' parameters gave low values (0.288 and 0.099). onversely, normal networks attained tumor-like characteristics (0.41 and 0.179) upon adaptation with 'tumor' parameters, including low conducted sensitivity, increased growth tendency, and elevated random biological variability. The deviant properties of tumor microcirculation seem to result largely from defective structural adaptation, with strongly reduced responses to conducted stimuli. Restoring conducted responses in tumor vasculature merits exploration as an approach to enhance the efficacy of radiation and chemotherapy.
3. Cardiovascular physiology and thermoregulation in humans in extreme environments
Project Leader: Hanns-Christian Gunga
Coworkers: Dr. Bergita Ganse, Dr. Andreas Werner, Matthias Steinach
The research is focussed on cardiovascular thermoregulatory adapatations in humans in extreme environments (desert, polar regions, space etc). Under these conditions, especially combined with high physical workloads and/or heavy armor protective clothing, the body core temperature can change rapidly, reaching deleterious levels. Therefore, in cooperation we recently developed and patented with the Draegerwerke AG a non-invasive heat flux measurement device (Double Sensor). With this device a continuous monitoring of core body temperature can now be achieved. Core temperature recordings combined with cardiovascular data and infrared scans were recently are applied during parabolic flights (figure 1) to determine mechanism of heat transfer under micro-g conditions. From 2009 on the heat flux sensor system (figure 2) will be used on the International Space Station (ISS) during VO2max measurements in astronauts to analyse short-, medium and long-term cardiovascular and thermoregulatory adaptations under mirco-g conditions for the first time. Furthermore, to keep normothermia in patients, i.e. to avoid hypo- or hyperthermic stages, studies are on-going to implement the system in clinical routines (surgery/anaesthesiology, new borne incubators). Center of Space Medicine Berlin
Berlin Bed Rest Study 2003/04 (Principal Investigator, Red blood cells), Parabolic Flight Campaign 2005 (Principal Investigator, thermoregulation), Parabolic Flight Campaign 2006 (Principal Investigator, Thermoregulation), Berlin Bed Rest Study 2007/08 (Principal Investigator, Thermoregulation, Red blood cells), Parabolic Flight Campaign 2007 (Principal Investigator, Fluid shift and thermoregulation)
4. Microvascular alterations induced by simulated micro-g
Project leader: Helmut Habazettl
Coworkers: Florian Adlberger
Collaborators: Bend Johannes, Deutsches Zentrum für Luft- und Raumfahrtforschung, Hamburg
Prolonged exposure to a micro-g environment as in space stations induces complex cardiovascular adaptations, which lead to disturbed temperature regulation and orthostatic dysfunction. In healthy subjects participating in the Berlin bed rest II study, which simulates micro-g by 60 days of 6° head down tilt bed rest, we investigated the responses of the skin microcirculation to physiologic stimuli. Laser-Doppler flow responses to endothelium dependent (acetylcholine ACh) and independent (Na-nitroprusside, SNP) vasodilators and to α- (phenylephrine) and ß2- (salbutamol) adrenoceptor specific agonists was assessed before and after bed rest. Drugs were locally applied by Drugs were locally applied by Drugs were locally applied by iontophoresis at 0.02 mA at a concentration of 1 %. After bedrest the ratio of flow increase induced by Ach over SNP was significantly decreased indicating deterioration of microvascular endothelial function. While the vaso-constrictive response to the α-agonist remained unchanged, dilation in response to the ß2-agonist increased. This may indicate upregulation of ß2-recptors due to the lack of sympathetic stimulation during bed rest. Also, insufficient peripheral vasoconstriction during orthostatic challenge after bed rest or micro-g may be partly due to increased sensitivity of the ß2-mediated dilatory response to sympathetic stimulation
5. Shear stress and vascular biology: regulation of FOXO1 and the angiopoietin-2/TIE2 system by shear stress
Project leader: Andreas Zakrzewicz
Coworkers: Luis Da Silva-Azevedo, Margret Hohberg, Sven Chlench, Christian Hoffmann
Collaborators: Theresa Pohlkamp, Universität Münster; Oliver Baum, Universität Bern
Transcription factor Foxo-1 can be inactivated via Akt-mediated phosphorylation. Since shear stress activates Akt, we determined whether Foxo-1 and the Foxo-1-dependent, angiogenesis-related Ang-2/Tie2-system are influenced by shear stress in endothelial cells. Expression of Foxo-1 and its target genes p27Kip1 and Ang-2 was decreased under shear stress (6 dyn/cm2, 24 h), nuclear exclusion of Foxo-1 by phosphorylation increased eNOS and Tie2 were up-regulated. No effects on Ang-1 expression were detected. Shear stress-dependent suppression of Ang-2 could be mimicked by siRNA against FoxO1.
In conclusion, Foxo-1 takes part in expression regulation of Ang-2 and both are part of the molecular response to shear stress, which may regulate angiogenesis.
6. Lung microvascular adaptation to acute and chronic hydrostatic stress
Project leader: Wolfgang M. Kübler
Coworkers : Jun Yin, Julia Hoffmann
Left-sided artial, ventricular, or valvular heart disease causes an acute of chronic elevation of hydrostatic pressure in the pulmonary microvasculature which becomes clinically manifest as acute cardiogenic pulmonary edema or chronic pulmonary hypertension with left heart disease. Structural and functional adaptations of lung endothelial, epithelial and smooth muscle cells contribute importantly to the pathophysiology of hydrostatic stress in the lung. We have shown that acute pressure stress activates transient receptor potential vanilloid 4 channels in lung endothelial cell, thus causing an influx of extracellularCa 2+ which promotes vascular barrier deterioration and the formation of lung edema. Simultaneously, Ca2+ influx triggers the endothelial synthesis of NO, which acts as an intercompartmental signalling molecule and blocks alveolar fluid absorption in adjacent alveolar epithelial cells, thus preventing the clearance of cardiogenic lung edema. Chronic pressure stress results in pulmonary hypertension characterized by lung vascular remodelling, media hypertrophy and endothelial dysfunction. Importantly, endothelial dysfunction is not caused by a loss of endothelial NO synthase, but by a functional adaptation of the endothelial phenotype in that the induction of mechanically or pharmacologically stimulated endothelial Ca2+ responses is markedly attenuated, presumably due to a structural adaptation of the endothelial cytoskeleton. Inhaled vasodilators present a novel and efficient therapeutic strategy in pulmonary hypertension with left heart disease, with aerosolized prostacyclin analogues being superior to inhaled nitric oxide. Yet, vasodilator treatment in left heart failure may be detrimental at increased cardiac output e.g. during exercise, when capillary pressure increases and promotes lung edema formation.
7. Novel antiangiogenic compounds derived from in silico screening for innovative approaches in cancer treatment
Project leader: Michael Höpfner
Coworkers: Robert Preissner, Bianca Nitzsche, Björn Hoffmann
Collaborators: Mark Schrader, Department of Urology, Charité; Matthias Ocker, Dept. of Med. I, University Hospital Erlangen
Almost 40 year ago, Folkman developed the concept of angiogenesis-dependent growth of solid tumors and postulated that the specific blocking of blood flow to the tumor may be a promising approach for cancer treatment.
The VEGF/VEGFR system and its related pathways play a pivotal role (tumor-)angiogenesis. Angiogenic vessels express elevated levels of VEGFRs, binding to VEGFs, which are excessively released by tumor cells. Thus, inhibition of VEGFR activity by specific tyrosine kinase inhibitors (TKI) has become a clinically relevant cancer treatment strategy. Searching for novel VEGFR-specific TKIs we used the conformational drug database "Super-Target". Checking two- and three-dimensional structural similarities to the clinically relevant VEGFR-TKI vatalanib as a lead structure, we identified promising candidate drugs and evaluated
their antiangiogenic and antiproliferative potency. In vitro and in vivo evaluations revealed that the novel compounds exert superior antiangiogenic, anti-proliferative and antimigratory effects on endo-thelial and urological cancer cells, as compared to the lead structure. The compounds are highly specific VEGFR-2 TKIs with IC50 values that were up to 10-fold lower than those of the lead structure. The antineoplastic mode of action of the novel compounds involved cell cycle arrest and induction of apoptosis, while unspecific cytotoxicity was not observed. First animal studies confirmed the good tolerability in vivo.
Thus, the identification of novel cancer drugs by use of in silico methods is a target-oriented and effective approach. The identified compounds effectively inhibit endothelial and tumor cell growth and merit further elucidation.