Our research group is interested in the biology and pathology of endothelial cells, with specific focus on the formation of new blood vessels angiogenesis during mouse development and in tumors. Several lines of evidence suggest that oxygen sensing in endothelial cells is of great importance for blood vessel growth and function. We are therefore studying the role of recently identified oxygen-sensitive signaling pathways in endothelial cells in various angiogenesis models.
Our approach is to combine in vitro and in vivo models, including transgenic and conditional knockout mice, to unravel the function of these signaling systems in endothelial cell growth, differentiation, and degeneration. This knowledge will be valuable for the development of novel therapeutic strategies aimed at fighting cancer, or promoting tissue regeneration. Myocardial ischemia and vessel degeneration are major challenges in aging populations.
Tissue factor expression in endothelial cells in health and : Blood Coagulation & Fibrinolysis
We are focussing on new approaches to prevent heart and vessel degeneration and to protect vascular function, particularly endothelial cell function. An early pathophysiological event in the development of atherosclerosis is endothelial dysfunction and vessel wall inflammation. A key compound modulating the underlying interaction of leukocytes and the endothelium is the nucleoside adenosine. Our goal is to clarify how various pharmacological, endogenous and dietary compounds may protect the endothelium via modulation of adenosine metabolism or membrane transport.
Another major issue in the context of vessel transplantation is the impact of cold storage on endothelial structure and function. We are testing newly designed solutions which better protect the endothelial cells during extended periods of cold storage. Recent progress of our lab documents the feasibility to maintain endothelial function of human vessel segments for more than 1 week, potentially benefitting vessel recipients with proper vessel grafts in the future. This team consists of staff with mainly technical background.
Dysregulation of endothelial cells is implicated in various cardiovascular diseases, including atherosclerosis. In particular, the endothelium regulates angiogenesis, the formation of new blood vessels.
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Endothelial cells express the receptors for pro-angiogenic growth factors, such as vascular endothelial growth factor VEGF and fibroblast growth factor FGF , which induce endothelial cells to proliferate and migrate to form vessels. Angiogenesis is important during development, but is also a significant factor in solid tumor growth. Solid tumors often induce angiogenesis to promote increased blood flow, which supports tumor growth and progression.
Therefore, targeted therapies like bevacizumab, which inhibits VEGF, are one approach to target tumor angiogenesis in the hopes of restricting blood flow to tumors.
Cardiovascular disease is the leading cause of death globally. Exposure to chemicals and toxins is one factor in development of cardiovascular disease, and it is becoming more appreciated that exposure to polychlorinated biphenyls, or PCBs, can cause detrimental health problems like hypertension and vascular inflammation.
Endothelial Cell Biology in Health and Disease
PCBs are organic chemicals that are presently banned in the US, but were manufactured and utilized for various commercial and industrial uses until While the proposed mechanism of PCB toxicity has been studied, there is little information about how miRNAs are involved. For example, surgical manipulations, changes in tissue demand, or arterial blockages that increase or decrease flow through a vessel result in outward or inward remodeling that return FSS closer to the original set point values These long-term changes are partly due to a process called entrenchment, where vasoconstriction or dilation are entrenched through matrix remodeling.
However, tissue remodeling also involves inflammation in which newly recruited monocytes and macrophages contribute cytokines, metalloproteinases, and extracellular matrix ECM proteins that are essential for the process 40 , A recent study showed that ECs exhibit an FSS set point such that flow within the physiological range suppresses inflammatory signaling and activates pathways that stabilize the vessel, whereas flow below or above the physiological range activates inflammatory pathways and suppresses the stabilization pathways 2.
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The set point model implies that different types of vessels arteries, veins, lymphatics that have very different flow magnitudes and patterns must have different set points. High flow has been shown to induce a distinct gene expression profile relative to normal flow; this expression profile contains both antiinflammatory and remodeling genes The identity of pathways that distinguish these two processes to determine the direction of remodeling remains a key, clinically relevant question.
Atherosclerosis is a chronic inflammatory disease of the arteries in which plaques develop in regions where flow is disturbed due to vessel geometry 12 , 47 , Straight segments of arteries with unidirectional, high laminar shear are actively protected from atherosclerosis due to induction of antiinflammatory, antioxidative, and antithrombotic genes, in large part through induction of the flow-dependent transcription factors KLF2 and nuclear factor erythroid-derived 2 —like 2 NRF2 By contrast, regions of arteries where time-averaged shear stress is low and subject to complex directional changes exhibit low, chronic inflammation even under control conditions, such as in WT mice that do not develop atherosclerosis Perhaps more importantly, this preexisting state sensitizes ECs to the action of other inflammatory mediators These results are consistent with studies showing that disease risk in vivo correlates with regions of low flow magnitude and with various metrics of flow disturbance 50 — Susceptibility to atherosclerosis also correlates with failure of the ECs to align in the flow direction Recently, however, it has been suggested that transverse flow i.
This in vivo result fits well with an in vitro study showing that flow perpendicular to the morphological and cytoskeletal axis of ECs activated inflammatory pathways, whereas flow that was parallel was antiinflammatory, even if it reversed direction The inflammatory effect of low or oscillatory flow can be rationalized by the fact that cells fail to align in these conditions; thus, even unidirectional flow will have a transverse component for a fraction of the cell population. This idea also fits well with the observation that onset of unidirectional laminar shear initially activates the inflammatory pathways, but these pathways are downregulated at later times as cells align and the antiinflammatory pathways become dominant The mechanistic basis for these effects is unknown, but a tantalizing clue comes from the finding that production of ROS by the NADPH oxidase complex in response to flow requires association of VE-cadherin with the oxidase complex through the polarity protein PAR3 Disturbed flow patterns induce inflammatory activation of the endothelium through a remarkably broad array of pathways and genes; see refs.
More recent work implicates multiple microRNAs in this process 58 , A fascinating connection between flow patterns, microRNAs, and lipid metabolism comes from studies of the cholesterol-regulated transcription factor sterol regulatory element—binding protein 2 SREBP2. Despite the diversity of inflammatory events triggered by disturbed flow, it should be kept in mind that the effects are not one-sided.
Disturbed flow also activates important negative regulators that suppress inflammation These findings are hardly surprising in light of the benign nature of disturbed flow in the absence of other risk factors.
Even with the presence of risk factors, disease generally takes many decades to manifest clinically. An interesting connection between atherosclerosis and physiological flow-dependent remodeling can be observed at the level of ECM remodeling. Normal endothelial basement membranes are composed mainly of collagen IV, laminin, and other glycoproteins and proteoglycans. Both flow-dependent remodeling and sprouting angiogenesis require proteolysis of this ECM and assembly of a fibronectin matrix 63 — Fibronectin also accumulates beneath the endothelium in atheroprone regions of arteries in normal adult mice, colocalized with inflammatory markers such as ICAM-1 or VCAM-1 Mechanistic in vitro studies have shown that fibronectin controls activation of multiple inflammatory mediators in response to disturbed flow 66 , 67 as well as oxidized LDL, another important inflammatory mediator in atherosclerosis Furthermore, fibronectin suppresses activation of eNOS and production of NO in response to flow 69 , thereby inducing endothelial dysfunction.
The importance of fibronectin in atherosclerosis is supported by animal studies demonstrating that genetic manipulations to reduce fibronectin in the vessel wall reduce plaque burden 70 — Interestingly, diabetes, which is a potent risk factor for atherosclerosis, further increases fibronectin deposition in atherosclerosis-prone regions of arteries Atherosclerosis may thus be seen as a form of flow-dependent remodeling that never resolves.
This idea could be tested by examining genetically modified mice with specific defects in flow sensing in both flow-dependent remodeling and atherosclerosis.
Identification of genes in humans and mice that control growth of collateral circulation after arterial blockage will allow comparison to the genes that control atherosclerosis and will provide a further, unbiased test of this hypothesis. Once plaques are formed, mechanical factors contribute to their continued remodeling.
Installation of a cuff on carotid arteries in hypercholesterolemic mice creates an upstream region of low, unidirectional flow and a downstream region of oscillatory flow Plaques formed in the upstream segments showed increased levels of markers of vulnerability, whereas the downstream region appeared more stable; however, the pressure drop across the restriction complicates the interpretation of these results. Thus, it is unknown to what extent high blood pressure contributes to the vulnerable phenotype in the upstream low-flow region compared to the downstream, oscillatory, low-pressure regions.
In other models, both low shear and transverse shear were strongly correlated with regions of vulnerability within plaques 77 — Plaque rupture itself also depends on wall strain.
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In particular, regions of low shear stress but high strain appear to be at greatest risk, presumably because of the combination of vulnerable plaque and high strain Microcalcification within a thin fibrous cap can also increase the risk of rupture, probably because of compliance mismatch, which generates regions of especially high strain Atherosclerotic lesions can restrict the artery lumen, but vessels respond by outward remodeling to maintain lumen diameter 82 , This process, often called the Glagov phenomenon, is a specific example of the FSS set point theory: blood vessels remodel to maintain a constant FSS 2 , One explanation for the failure to maintain lumen diameter is that fibrous connective tissue of the adventitia could serve as a physical barrier to further expansion and stiffening of the adventitia under loading 84 or local inflammation, and thickening of the adventitia in atherosclerosis 85 could contribute to this effect.
The recent observation that ECs undergo an endothelial-mesenchymal transition EndMT in response to proatherogenic flow and inflammatory cytokines present in atherosclerotic lesions might also explain this phenomenon 86 , EndMT results in reduced expression of endothelial-specific molecules including VE-cadherin and PECAM-1, which mediate flow sensing and could prevent flow-dependent remodeling.
Outward remodeling has been linked to plaque vulnerability 89 , 90 , perhaps through increased expression of metalloproteinases that mediate remodeling but also degrade collagen in the fibrous cap. However, a recent large-cohort study addressing the role of lesion remodeling in major adverse cardiac events found that lesions with multiple necrotic cores and thin fibrous caps were more prevalent in the context of inward remodeling Upon artery occlusion, blood flow is redirected into smaller collateral vessels upstream of the lesion site, which induces enlargement of these small vessels, to improve perfusion of the surrounding tissue Increased collateral flow is also promoted by the arterialization of preexisting capillaries 93 , Collateral circulation, characterized clinically as the collateral flow index, is a major determinant of favorable outcome after myocardial infarction.