Abstract:The transformation of the regular vasculature in normal tissue into a highly inhomogeneous tumor specific capillary network is described by a theoretical model

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A theoretical model based on the molecular interactions between a growing tumor and a dynamically evolving blood vessel network describes the transformation of the regular vasculature in normal tissues into a highly inhomogeneous tumor specific capillary network. The emerging morphology, characterized by the compartmentalization of the tumor into several regions differing in vessel density, diameter, and necrosis, is in accordance with experimental data for human melanoma. Vessel collapse due to a combination of severely reduced blood flow and solid stress exerted by the tumor leads to a correlated percolation process that is driven towards criticality by the mechanism of hydrodynamic vessel stabilization.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d m a n u s c r i p t AbstractWe formulate a theoretical model to analyse the vascular remodelling process of an arterio-venous vessel network during solid tumour growth. The model incorporates a hierarchically organized initial vasculature comprising arteries, veins and capillaries, and involves sprouting angiogenesis, vessel cooption, dilation and regression as well as tumour cell proliferation and death. The emerging tumour vasculature is non-hierarchical, compartmentalized into well characterized zones and transports efficiently an injected drug-bolus. It displays a complex geometry with necrotic zones and "hot spots" of increased vascular density and blood flow of varying size. The corresponding cluster size distribution is algebraic, reminiscent of a self-organized critical state.The intra-tumour vascular-density fluctuations correlate with pressure drops in the initial vasculature suggesting a physical mechanism underlying hot-spot formation.

Summary: Both thrombin and plasmin induce contraction of brain endothelial cells, which may increase capillary perme ability thereby leading to disruption of the blood-brain barrier. Identification of thrombin receptors, as well as the influence of plasmin on their activation, in capillary endothelial cells and astrocytes are therefore essential for understanding injury related actions of thrombin in the brain. Using the reverse transcriptase-polymerase chain reaction method, the present study shows that primary cultures of rat brain capillary endo thelial (RBCE) cells and astrocytes derived from rat brain ex press two different thrombin receptors. The first is proteolyti cally activated receptor (PAR)-l, the receptor responsible for the vast majority of the thrombin's cellular activation func tions; the second is PAR-3, a receptor described to be essential for normal responsiveness to thrombin in mouse platelets. In addition to these thrombin receptors, the mRNA (messenger RNA) for PAR-2, a possible trypsin receptor, was also identi fied. Functional significance of thrombin receptors was indi cated by changes in rCa 2 +l; in response to thrombin, as mea sured by FURA-2 fluorescence in RBCE cells. Thrombin as low as 4 nmollL induced an abrupt increase in lCa 2 +1i whereas, Thrombosis is of paramount importance in the patho physiology of ischemic stroke. Thrombogenic and fibri nolytic enzymes accumulating in the occluded vascular segments may play a role in the opening of the blood brain barrier, and the subsequent exposure of cells in the brain to high amounts of thrombin and plasmin is likely to have deleterious effects. Thrombin actions are largely mediated by PAR-I, the first member of the proteolyti-