The endothelial cell (EC) lining of the pulmonary vasculature forms a semipermeable barrier between the blood and the interstitium of the lung. Disruption of this barrier occurs during inflammatory...

Cytoskeletal regulation of pulmonary vascular permeability

Although vascular endothelial growth factor (VEGF) induces angiogenesis, it also disrupts vascular barrier function in diseased tissues. Accordingly, VEGF expression in cancer and ischaemic disease has unexpected pathophysiological consequences. By uncoupling endothelial cell-cell junctions VEGF causes vascular permeability and oedema, resulting in extensive injury to ischaemic tissues after stroke or myocardial infarction. In cancer, VEGF-mediated disruption of the vascular barrier may potentiate tumour cell extravasation, leading to widespread metastatic disease. Therefore, by blocking the vascular permeability promoting effects of VEGF it may be feasible to reduce tissue injury after ischaemic disease and minimize the invasive properties of circulating tumour cells.

Pathophysiological consequences of VEGF-induced vascular permeability

For a systemically administered therapeutic agent to reach neoplastic cells, it must enter the blood circulation, cross the vessel wall, move through the extracellular matrix and avoid getting cleared by the lymphatics. In tumours, each of these barriers is abnormal, changes with space and time, and depends on host-tumour interactions. Intravital microscopy has provided unprecedented molecular, cellular, anatomical and functional insights into these barriers and has revealed new approaches to improved detection and treatment.

Dissecting tumour pathophysiology using intravital microscopy

Preclinical and clinical evidence shows that antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel "normalization." The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with antiangiogenic therapy. By using a mathematical model to simulate IFP and IFV profiles in tumors, we show here that antiangiogenic therapy can decrease IFP by decreasing the tumor size, vascular hydraulic permeability, and/or the surface area per unit tissue volume of tumor vessels. Within a certain window of antiangiogenic effects, interstitial convection within the tumor can increase dramatically, whereas fluid convection out of the tumor margin decreases. This would result in increased drug convection within the tumor and decreased convection of drugs, growth factors, or metastatic cancer cells from the tumor margin into the peritumor fluid or tissue. Decreased convection of growth factors, such as vascular endothelial growth factor-C (VEGF-C), would limit peritumor hyperplasia, and decreased VEGF-A would limit angiogenesis in sentinel lymph nodes. Both of these effects would reduce the probability of lymphatic metastasis. Finally, decreased fluid convection into the peritumor tissue would decrease peritumor edema associated with brain tumors and ascites accumulation in the peritoneal or pleural cavity, a major complication with a number of malignancies.

http://cancerres.aacrjournals.org/content/canres/67/6/2729.full.pdf

Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model.

Diffusion and convection in collagen gels: implications for transport in the tumor interstitium.

Effect of vascular endothelial growth factor on cultured endothelial cell monolayer transport properties.

Erythrocytes enhance lymphocyte rolling and arrest in vivo.

Kinetics of placenta growth factor/vascular endothelial growth factor synergy in endothelial hydraulic conductivity and proliferation.

Physical interactions between circulating cells and the vascular wall play a central role in inflammation, metastasis, atherosclerosis, and therapeutic cell delivery. Unfortunately, traditional in vitro flow assays cannot be used to visualize the details of cell-surface interactions in blood flow because of inappropriate geometry and the poor penetration of light in erythrocyte solutions. To overcome these obstacles, we have developed an agarose-cast cylindrical vessel system to examine the profiles of cells interacting with surfaces under flow conditions. This design allows observation and quantification of cell deformation as cells adhere to surfaces under dynamic flow conditions without modifying the microscope or optical path. Furthermore, our flow system is uniquely suited for monitoring the profiles of adherent leukocytes deforming in response to erythrocyte suspension flow. We have used this flow system to study the role of erythrocytes in leukocyte-substrate interactions. Our results show that the cell deformation index (the ratio of the cell length to cell height) is higher in erythrocyte solutions compared to erythrocyte-free saline. This novel lateral view flow system provides a powerful technique for visualizing and quantifying the morphological changes of cells in contact with substrates exposed to shear stress.

https://www.future-science.com/doi/pdf/10.2144/01302rr02

Lateral view flow system for studies of cell adhesion and deformation under flow conditions.

Interactions between circulating cells and the vascular wall play a central role in inflammation, metastasis and therapeutic cell delivery. Unfortunately, traditional in vitro flow assays cannot be used to study the effect of blood rheology on cell-surface interactions because of inappropriate geometry and poor penetration of light in erythrocyte solutions. To overcome these limitations, we have developed an agarose-cast vessel system to examine the profiles of cells interacting with surfaces under flow conditions. This design allows observation and quantification of cell deformation, rolling and binding under conditions of dynamic flow without modifying the microscope or optical path. Our results show that the cell deformation index (the ratio of the cell length to cell height) is higher in the presence of erythrocytes, as opposed to saline without erythrocytes.

Jin Yuan

Papers

Effect of vascular endothelial growth factor on cultured endothelial cell monolayer transport properties.

Erythrocytes enhance lymphocyte rolling and arrest in vivo.

Kinetics of placenta growth factor/vascular endothelial growth factor synergy in endothelial hydraulic conductivity and proliferation.

Lateral view flow system for studies of cell adhesion and deformation under flow conditions.

Development of a lateral view flow system for studies of cell deformation under flow conditions