Origins of Metabolic Signals

Diameters of microvessels undergo continuous structural adaptation in response to hemodynamic and metabolic stimuli. To ensure adequate flow distribution, metabolic responses are needed to increase diameters of vessels feeding poorly perfused regions. Possible modes of metabolic control include release of signaling substances from vessel walls, from the supplied tissue and from red blood cells (RBC). Here, a theoretical model was used to compare the abilities of these metabolic control modes to provide adequate tissue oxygenation, and to generate blood flow velocities in agreement with experimental observations. Structural adaptation of vessel diameters was simulated for an observed mesenteric network structure in the rat with 576 vessel segments. For each mode of metabolic control, resulting distributions of oxygen and deviations between simulated and experimentally observed flow velocities were analyzed. It was found that wall-derived and tissue-derived growth signals released in response to low oxygen levels could ensure adequate oxygen supply, but RBC- derived signals caused inefficient oxygenation. Closest agreement between predicted and observed flow velocities was obtained with wall-derived growth signals proportional to vessel length. Adaptation in response to oxygen- independent release of a metabolic signal substance from vessel walls or the supplied tissue was also shown to be effective for ensuring tissue oxygenation due to a dilution effect if growth signal substances are released into the blood. The present results suggest that metabolic signals responsible for structural adaptation of microvessel diameters are derived from vessel walls or from perivascular tissue

Chronic kidney disease induces a systemic microangiopathy, tissue hypoxia and dysfunctional angiogenesis

Chronic kidney disease (CKD) is associated with excessive mortality from cardiovascular disease (CVD). Endothelial dysfunction, an early manifestation of CVD, is consistently observed in CKD patients and might be linked to structural defects of the microcirculation including microvascular rarefaction. However, patterns of microvascular rarefaction in CKD and their relation to functional deficits in perfusion and oxygen delivery are currently unknown. In this in-vivo microscopy study of the cremaster muscle microcirculation in BALB/c mice with moderate to severe uremia, we show in two experimental models (adenine feeding or subtotal nephrectomy), that serum urea levels associate incrementally with a distinct microangiopathy. Structural changes were characterized by a heterogeneous pattern of focal microvascular rarefaction with loss of coherent microvascular networks resulting in large avascular areas. Corresponding microvascular dysfunction was evident by significantly diminished blood flow velocity, vascular tone, and oxygen uptake. Microvascular rarefaction in the cremaster muscle paralleled rarefaction in the myocardium, which was accompanied by a decrease in transcription levels not only of the transcriptional regulator HIF-1 alpha, but also of its target genes Angpt-2, TIE-1 and TIE-2, Flkt-1 and MMP-9, indicating an impaired hypoxia-driven angiogenesis. Thus, experimental uremia in mice associates with systemic microvascular disease with rarefaction, tissue hypoxia and dysfunctional angiogenesis

analysis by mathematical model simulations

Blutgefäße sind in der Lage, ihre Struktur kontinuierlich an wechselnde Bedingungen und funktionelle Anforderungen anzupassen (Angioadaptation). Hierfür müssen für alle Gefäße genetisch determinierte Reaktionsmuster (Adaptationsregeln) existieren. Für die Analyse dieser Adaptationsregeln sind reduktionistische Untersuchungsansätze allein nicht hinreichend, um die komplexen Wechselwirkungsbeziehungen in Gefäßnetzwerken abzubilden. In den vorliegenden Studien wurden deshalb biologische Experimente mit theoretischen Modellsimulationen kombiniert. Als biologische Ausgangs- und Vergleichsdaten wurden mit Hilfe der Intravitalmikroskopie Parametersätze aller Gefäße (u. a. Durchmesser, Strömungsgeschwindigkeit, Topologie) von Mikrogefäßnetzwerken bestimmt. Die theoretischen Analysen wurden mit einem in der Arbeitsgruppe entwickelten mathematischen Modell der strukturellen Durchmesseradaptation durchgeführt, das im Rahmen der vorliegenden Studien weiterentwickelt und auf zusätzliche Fragestellungen angewandt wurde. In diesem Modell reagieren alle Gefäße gemäß einem einheitlichen Satz von Adaptationsregeln auf Stimuli, die von hämodynamischen (Blutströmung, Wandschubspannung, transmuraler Druck, Wandspannung) und metabolischen (Sauerstoffpartialdruck) Bedingungen abgeleitet werden. In dieser Arbeit werden drei Studien zur strukturellen vaskulären Adaptation zusammengefasst. (A) Die Rolle verschiedener Mechanismen des Informationstransfers (hämodynamische Kopplung über Blutströmung und Druck, Konvektion von Sauerstoff und anderen Metaboliten im Blut, Konduktion vasoaktiver Stimuli entlang der Gefäßwände) für die Netzwerkadaptation wurde durch selektive Blockade dieser Mechanismen in dem Modell („mathematical knockout“) untersucht. Die Ergebnisse weisen darauf hin, dass die hämodynamische Kopplung über Blutströmung der wesentliche Mechanismus des Informationstransfers für die strukturelle Anpassung auf Änderungen des kapillären Sauerstoffbedarfs ist (Pries et al., Am J Physiol 2003 Jun; 284(6):H2204-12). (B) Das vorhandene Modell der Durchmesseradaptation wurde zu einem integrierten Modell der Adaptation von Gefäßdurchmesser und -wanddicke weiterentwickelt. Somit können erstmalig die in vivo beobachteten Verteilungen beider Parameter in Gefäßnetzwerken durch wenige und einfache Adaptationsregeln erklärt werden. Die mit dem Modell mögliche Analyse von hämodynamischem Widerstand und mikrovaskulärer Wandstruktur in Gefäßnetzwerken ist u. a. von Bedeutung für das Verständnis der arteriellen Hypertonie (Pries et al., Hypertension. 2005 Oct; 46(4):725-31). (C) Die Lokalisation von Sauerstoffsensoren wurde mit dem Modell der Durchmesseradaptation untersucht, das um die Simulation der Diffusion von Sauerstoff und vasoaktiven Metaboliten im Gewebe erweitert wurde. Obwohl experimentelle Befunde die Freisetzung vasoaktiver Substanzen in Reaktion auf einen niedrigen Sauerstoffgehalt für Gewebe, Gefäßwand und Erythrozyten gezeigt haben, legen die Ergebnisse nahe, dass überraschenderweise die Gefäßwand die zentrale Rolle in der metabolischen Kontrolle der strukturellen Gefäßdurchmesser spielt (Reglin et al., Am J Physiol 2009 Dec; 297(6):H2206 19).Vessel segments are capable of continuous adaptive structural changes in response to varying conditions and functional demands (angioadaptation). This requires genetically determined reaction patterns (adaptation rules) for all vessels. The understanding of these adaptation rules is not readily achieved using reductionist experimental approaches because of the complex functional interactions within microvascular networks. Thus, in the present studies biological experiments were combined with theoretical model simulations. Parameter sets of all vessel segments (among others diameter, flow velocity, topology) of microvascular networks were determined by intravital microscopy and served as model input and for comparison of model output values. For theoretical analysis, an existing mathematical model of structural vessel diameter adaptation was used, which was developed and applied to additional questions in the present studies. In the model, all vessels respond to stimuli derived from hemodynamic (blood flow, wall shear stress, transmural pressure, wall stress) and metabolic (oxygen partial pressure) conditions according to a uniform set of adaptation rules. Here, three studies analyzing structural vascular adaptation are combined. (A) The role of various mechanisms of information transfer (hemodynamic coupling by blood flow and pressure, convection of oxygen and other metabolites with the blood, conduction of vasoactive stimuli along vessel walls) for network adaptation was studied by selectively blocking these mechanisms in the model (“mathematical knockout”). The results indicate, that hemodynamic coupling by blood flow is the main mechanisms of information transfer for structural adaptation to changes in capillary oxygen demand (Pries et al., Am J Physiol 2003 Jun; 284(6):H2204-12). (B) The existing model was advanced to an integrated adaptation model of vascular diameter and wall thickness. Thus, for the first time distributions of both parameters in vascular networks observed in vivo can be explained by a restricted set of elementary adaptation rules. The analysis of hemodynamic flow resistance and microvascular wall structure in vascular networks with the model is relevant for understanding arterial hypertension (Pries et al., Hypertension. 2005 Oct; 46(4):725-31). (C) Localization of oxygen sensors was analyzed using the model of diameter adaptation, extended by the simulation of diffusion of oxygen and vasoactive metabolites in the tissue. Though experimental studies have shown the release of vasoactive substances in response to low oxygen content in tissue, vessel wall and erythrocytes, present results suggest that surprisingly the vessel wall seems to play the central role in the metabolic control of structural vessel diameter (Reglin et al., Am J Physiol 2009 Dec; 297(6):H2206-19)

Structural Control of Microvessel Diameters: Origins of Metabolic Signals

Diameters of microvessels undergo continuous structural adaptation in response to hemodynamic and metabolic stimuli. To ensure adequate flow distribution, metabolic responses are needed to increase diameters of vessels feeding poorly perfused regions. Possible modes of metabolic control include release of signaling substances from vessel walls, from the supplied tissue and from red blood cells (RBC). Here, a theoretical model was used to compare the abilities of these metabolic control modes to provide adequate tissue oxygenation, and to generate blood flow velocities in agreement with experimental observations. Structural adaptation of vessel diameters was simulated for an observed mesenteric network structure in the rat with 576 vessel segments. For each mode of metabolic control, resulting distributions of oxygen and deviations between simulated and experimentally observed flow velocities were analyzed. It was found that wall-derived and tissue-derived growth signals released in response to low oxygen levels could ensure adequate oxygen supply, but RBC-derived signals caused inefficient oxygenation. Closest agreement between predicted and observed flow velocities was obtained with wall-derived growth signals proportional to vessel length. Adaptation in response to oxygen-independent release of a metabolic signal substance from vessel walls or the supplied tissue was also shown to be effective for ensuring tissue oxygenation due to a dilution effect if growth signal substances are released into the blood. The present results suggest that metabolic signals responsible for structural adaptation of microvessel diameters are derived from vessel walls or from perivascular tissue.National Institutes of Health [HL034555]; Schuchtermann-Foundation (Germany, Dortmund)This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Structural Control of Microvessel Diameters: Origins of Metabolic Signals

Diameters of microvessels undergo continuous structural adaptation in response to hemodynamic and metabolic stimuli. To ensure adequate flow distribution, metabolic responses are needed to increase diameters of vessels feeding poorly perfused regions. Possible modes of metabolic control include release of signaling substances from vessel walls, from the supplied tissue and from red blood cells (RBC). Here, a theoretical model was used to compare the abilities of these metabolic control modes to provide adequate tissue oxygenation, and to generate blood flow velocities in agreement with experimental observations. Structural adaptation of vessel diameters was simulated for an observed mesenteric network structure in the rat with 576 vessel segments. For each mode of metabolic control, resulting distributions of oxygen and deviations between simulated and experimentally observed flow velocities were analyzed. It was found that wall-derived and tissue-derived growth signals released in response to low oxygen levels could ensure adequate oxygen supply, but RBC-derived signals caused inefficient oxygenation. Closest agreement between predicted and observed flow velocities was obtained with wall-derived growth signals proportional to vessel length. Adaptation in response to oxygen-independent release of a metabolic signal substance from vessel walls or the supplied tissue was also shown to be effective for ensuring tissue oxygenation due to a dilution effect if growth signal substances are released into the blood. The present results suggest that metabolic signals responsible for structural adaptation of microvessel diameters are derived from vessel walls or from perivascular tissue