Cyclic strain disrupts endothelial network formation on Matrigel

Most forms of tissue healing depend critically on revascularisation. In soft tissues and in vitro, mechanical stimuli have been shown to promote vessel-forming activity. However, in bone defects, increased interfragmentary motion impairs vascular regeneration. Because these effects seem contradictory, we aimed to determine whether a range of mechanical stimuli exists in which angiogenesis is favoured. A series of cyclic strain magnitudes were applied to a Matrigel-based “tube formation” assay and the total lengths of networks formed by human microvascular endothelial cells measured at 24 h. Network lengths were reduced at all strain levels, compared to unstretched controls. However, the levels of pro-angiogenic matrix metalloproteases-2 and -9 in the corresponding conditioned media were unchanged by strain, and vascular endothelial growth factor was uniformly elevated in stretched conditions. By repeating the assay with the addition of conditioned media from mesenchymal stem cells cultivated in similar conditions, paracrine stimuli were shown to increase network lengths, but not to alter the negative effect of cyclic stretching. Together, these results demonstrate that directly applied periodic strains can inhibit endothelial organisation in vitro, and suggest that this may be due to physical disruption rather than biochemical modulation. Most importantly, the results indicate that the straining of endothelial cells and their assembly into vascular-like structures must be studied simultaneously to adequately characterise the mechanical influence on vessel formation.

Mechanical influences on endothelial cell network formation in vitro

While both the restoration of the blood supply and an appropriate local mechanical environment are critical for uneventful bone healing, their influence on each other remains unclear. Human bone fracture haematomas (<72h post-trauma) were cultivated for 3 days in fibrin matrices, with or without cyclic compression. Conditioned medium from these cultures enhanced the formation of vessel-like networks by HMEC-1 cells, and mechanical loading further elevated it, without affecting the cells’ metabolic activity. While haematomas released the angiogenesis-regulators, VEGF and TGF-β1, their concentrations were not affected by mechanical loading. However, direct cyclic stretching of the HMEC-1 cells decreased network formation. The appearance of the networks and a trend towards elevated VEGF under strain suggested physical disruption rather than biochemical modulation as the responsible mechanism. Thus, early fracture haematomas and their mechanical loading increase the paracrine stimulation of endothelial organisation in vitro, but direct periodic strains may disrupt or impair vessel assembly in otherwise favourable conditions.

VEGFR-3 and Tie pathways in vascular network formation

The blood and lymphatic vascular systems are essential for life, but they may become harnessed for sinister purposes in pathological conditions. For example, tumors learn to grow a network of blood vessels (angiogenesis), securing a source of oxygen and nutrients for sustained growth. On the other hand, damage to the lymph nodes and the collecting lymphatic vessels may lead to lymphedema, a debilitating condition characterized by peripheral edema and susceptibility to infections. Promoting the growth of new lymphatic vessels (lymphangiogenesis) is an attractive approach to treat lymphedema patients. Angiopoietin-1 (Ang1), a ligand for the endothelial receptor tyrosine kinases Tie1 and Tie2. The Ang1/Tie2 pathway has previously been implicated in promoting endothelial stability and integrity of EC monolayers. The studies presented here elucidate a novel function for Ang1 as a lymphangiogenic factor. Ang1 is known to decrease the permeability of blood vessels, and could thus act as a more global antagonist of plasma leakage and tissue edema by promoting growth of lymphatic vessels and thereby facilitating removal of excess fluid and other plasma components from the interstitium. These findings reinforce the idea that Ang1 may have therapeutic value in conditions of tissue edema. VEGFR-3 is present on all endothelia during development, but in the adult its expression becomes restricted to the lymphatic endothelium. VEGF-C and VEGF-D are ligands for VEGFR-3, and potently promote lymphangiogenesis in adult tissues, with direct and remarkably specific effects on the lymphatic endothelium in adult tissues. The data presented here show that VEGF-C and VEGF-D therapy can restore collecting lymphatic vessels in a novel orthotopic model of breast cancer-related lymphedema. Furthermore, the study introduces a novel approach to improve VEGF-C/VEGF-D therapy by using engineered heparin-binding forms of VEGF-C, which induced the rapid formation of organized lymphatic vessels. Importantly, VEGF-C therapy also greatly improved the survival and integration of lymph node transplants. The combination of lymph node transplantation and VEGF-C therapy provides a basis for future therapy of lymphedema. In adults, VEGFR-3 expression is restricted to the lymphatic endothelium and the fenestrated endothelia of certain endocrine organs. These results show that VEGFR-3 is induced at the onset of angiogenesis in the tip cells that lead the formation of new vessel sprouts, providing a tumor-specific vascular target. VEGFR-3 acts downstream of VEGF/VEGFR-2 signals, but, once induced, can sustain angiogenesis when VEGFR-2 signaling is inhibited. The data presented here implicate VEGFR-3 as a novel regulator of sprouting angiogenesis along with its role in regulating lymphatic vessel growth. Targeting VEGFR-3 may provide added efficacy to currently available anti-angiogenic therapeutics, which typically target the VEGF/VEGFR-2 pathway.

Monte Carlo simulation of network formation based on structural fragments in epoxy-anhydride systems

A method combining the Monte Carlo technique and the simple fragment approach has been developed for simulating network formation in amine-catalysed epoxy-anhydride systems. The method affords a detailed insight into the nature and composition of the network, showing the distribution of various fragments. It has been used to characterize the network formation in the reaction of the diglycidyl ester of isophthalic acid with hexahydrophthalic anhydride, catalysed by benzyldimethylamine. Pre-gel properties like number and weight distributions and average molecular weights have been calculated as a function of epoxy conversion, leading to a prediction of the gel-point conversion. Analysis of the simulated network further yields other characteristic properties such as concentration of crosslink points, distribution and concentration of elastically active chains, average molecular weight between crosslinks, sol content and mass fraction of pendent chains. A comparison has been made of the properties obtained through simulation with those predicted by the fragment approach alone, which, however, gives only average properties. The Monte Carlo simulation results clearly show that loops and other cyclic structures occur in the gel. This may account for the differences observed between the results of the simulation and the fragment model in the post-gel phase. Copyright (C) 1996 Elsevier Science Ltd.

Kinetics of copolyurethane network formation

Cure kinetics for the formation of copolyurethane networks of various compositions based on hydroxy-terminated polybutadiene(HTPB), poly(12-hydroxy stearic acid-co-TMP) ester polyol(PEP), and different isocyanates has been studied through viscosity build up during the cure reaction. The viscosity (N)-time (t) plots conform to the equation N = ae(bt), where a and b are empirical constants, dependent on the composition and the nature of the polyols and the isocyanates. The rate constants (b) for viscosity build up, evaluated from the slopes of dN/dt versus N plots at different temperatures, were found to vary significantly from 0.0073 to 0.25 min(-1); and the activation energies for gelation were found to be in the range 20 to 40 kJ mol(-1). The results have been interpreted in terms of the dependence of the rate constants on structural characteristics of the prepolymers. (C) 1997 John Wiley & Sons, Inc.

Expected Fair Allocation in Farsighted Network Formation

I consider cooperation situations where players have network relations. Networks evolve according to a stationary transition probability matrix and at each moment in time players receive payoffs from a stationary allocation rule. Players discount the future by a common factor. The pair formed by an allocation rule and a transition probability matrix is called expected fair if for every link in the network both participants gain, marginally, and in discounted, expected terms, the same from it; and it is called a pairwise network formation procedure if the probability that a link is created (or eliminated) is positive if the discounted, expected gains to its two participants are positive too. The main result is the existence, for the discount factor small enough, of an expected fair and pairwise network formation procedure where the allocation rule is component balanced, meaning it distributes the total value of any maximal connected subnetwork among its participants. This existence result holds for all discount factors when the pairwise network formation procedure is restricted. I finally provide some comparison with previous models of farsighted network formation.

A Unifying model of strategic network formation

Documento de trabajo

Efficiency vs. Stability in a Mixed Network Formation Model

Documentos de Trabajo

The impact of liberalizing cost-saharing on basic models of network formation

This paper studies the impact of "liberalizing " the cost-sharing of links on some basic models of network formation. This is done in a setting where both doubly supported and singly supported links are possible, and which includes the two seminal models of network formation by Jackson and Wolinsky and Bala and Goyal as extreme cases. In this setting, the notion of pairwise stability is extended and it is proved that liberalizing cost-sharing for doubly supported links widens the range of values of the parameters where the efficient networks formed by such type of links are pairwise stable, while the range of values of the parameters where the efficient networks formed by singly supported links are pairwise stable shrinks, but the region where the latter are e¢ cient and pairwise stable remains the same.

CD45+ Cells Present Within Mesenchymal Stem Cell Populations Affect Network Formation of Blood-Derived Endothelial Outgrowth Cells.

Mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) represent promising cell sources for angiogenic therapies. There are, however, conflicting reports regarding the ability of MSCs to support network formation of endothelial cells. The goal of this study was to assess the ability of human bone marrow-derived MSCs to support network formation of endothelial outgrowth cells (EOCs) derived from umbilical cord blood EPCs. We hypothesized that upon in vitro coculture, MSCs and EOCs promote a microenvironment conducive for EOC network formation without the addition of angiogenic growth supplements. EOC networks formed by coculture with MSCs underwent regression and cell loss by day 10 with a near 4-fold and 2-fold reduction in branch points and mean segment length, respectively, in comparison with networks formed by coculture vascular smooth muscle cell (SMC) cocultures. EOC network regression in MSC cocultures was not caused by lack of vascular endothelial growth factor (VEGF)-A or changes in TGF-β1 or Ang-2 supernatant concentrations in comparison with SMC cocultures. Removal of CD45+ cells from MSCs improved EOC network formation through a 2-fold increase in total segment length and number of branch points in comparison to unsorted MSCs by day 6. These improvements, however, were not sustained by day 10. CD45 expression in MSC cocultures correlated with EOC network regression with a 5-fold increase between day 6 and day 10 of culture. The addition of supplemental growth factors VEGF, fibroblastic growth factor-2, EGF, hydrocortisone, insulin growth factor-1, ascorbic acid, and heparin to MSC cocultures promoted stable EOC network formation over 2 weeks in vitro, without affecting CD45 expression, as evidenced by a lack of significant differences in total segment length (p=0.96). These findings demonstrate the ability of MSCs to support EOC network formation correlates with removal of CD45+ cells and improves upon the addition of soluble growth factors.

Bounded Rationality and Repeated Network Formation

We define a finite-horizon repeated network formation game with consent and study the differences induced by two levels of individual rationality. Perfectly rational players will remain unconnected at the equilibrium, while nonempty equilibrium networks may form when players are assumed to behave as finite automata of limited complexity. We provide structural properties of the sequences of networks which are likely to form in Nash and subgame perfect Nash equilibria of the repeated game. For instance, players can form totally different connected networks at each period or the sequence of networks can exhibit a total order relationship.

Network formation under mutual consent and costly communication

We consider two different approaches to describe the formation of social networks under mutual consent and costly communication. First, we consider a network-based approach; in particular Jackson–Wolinsky’s concept of pairwise stability. Next, we discuss a non-cooperative game-theoretic approach, through a refinement of the Nash equilibria of Myerson’s consent game. This refinement, denoted as monadic stability, describes myopically forward looking behavior of the players. We show through an equivalence that the class of monadically stable networks is a strict subset of the class of pairwise stable networks that can be characterized fully by modifications of the properties defining pairwise stability.

Nash equilibria of network formation games under consent

We investigate the Nash equilibria of game theoretic models of network formation based on explicit consent in link formation. These so-called “consent models” explicitly take account of link formation costs. We provide characterizations of Nash equilibria of such consent models under both one-sided and two-sided costs of link formation. We relate these equilibrium concepts to link-based stability concepts, in particular strong link deletion proofness.

A game-theoretic network formation model

We study the dynamics of a game-theoretic network formation model that yields large-scale small-world networks. So far, mostly stochastic frameworks have been utilized to explain the emergence of these networks. On the other hand, it is natural to seek for game-theoretic network formation models in which links are formed due to strategic behaviors of individuals, rather than based on probabilities. Inspired by Even-Dar and Kearns (2007), we consider a more realistic model in which the cost of establishing each link is dynamically determined during the course of the game. Moreover, players are allowed to put transfer payments on the formation of links. Also, they must pay a maintenance cost to sustain their direct links during the game. We show that there is a small diameter of at most 4 in the general set of equilibrium networks in our model. Unlike earlier model, not only the existence of equilibrium networks is guaranteed in our model, but also these networks coincide with the outcomes of pairwise Nash equilibrium in network formation. Furthermore, we provide a network formation simulation that generates small-world networks. We also analyze the impact of locating players in a hierarchical structure by constructing a strategic model, where a complete b-ary tree is the seed network.