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Endothelial cell phenotypic behaviors cluster into dynamic state transition programs modulated by angiogenic and angiostatic cytokines.

ABSTRACT: Angiogenesis requires coordinated dynamic regulation of multiple phenotypic behaviors of endothelial cells in response to environmental cues. Multi-scale computational models of angiogenesis can be useful for analyzing effects of cell behaviors on the tissue level outcome, but these models require more intensive experimental studies dedicated to determining the required quantitative "rules" for cell-level phenotypic responses across a landscape of pro- and anti-angiogenic stimuli in order to ascertain how changes in these single cell responses lead to emerging multi-cellular behavior such as sprout formation. Here we employ single-cell microscopy to ascertain phenotypic behaviors of more than 800 human microvascular endothelial cells under various combinational angiogenic (VEGF) and angiostatic (PF4) cytokine treatments, analyzing their dynamic behavioral transitions among sessile, migratory, proliferative, and apoptotic states. We find that an endothelial cell population clusters into an identifiable set of a few distinct phenotypic state transition patterns (clusters) that is consistent across all cytokine conditions. Varying the cytokine conditions, such as VEGF and PF4 combinations here, modulates the proportion of the population following a particular pattern (referred to as phenotypic cluster weights) without altering the transition dynamics within the patterns. We then map the phenotypic cluster weights to quantified population level sprout densities using a multi-variate regression approach, and identify linear combinations of the phenotypic cluster weights that associate with greater or lesser sprout density across the various treatment conditions. VEGF-dominant cytokine combinations yielding high sprout densities are characterized by high proliferative and low apoptotic cluster weights, whereas PF4-dominant conditions yielding low sprout densities are characterized by low proliferative and high apoptotic cluster weights. Migratory cluster weights show only mild association with sprout density outcomes under the VEGF/PF4 conditions and the sprout formation characteristics explored here.

SUBMITTER: Rimchala T

PROVIDER: S-EPMC3581728 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Endothelial cell phenotypic behaviors cluster into dynamic state transition programs modulated by angiogenic and angiostatic cytokines.

Rimchala Tharathorn T Kamm Roger D RD Lauffenburger Douglas A DA

Integrative biology : quantitative biosciences from nano to macro 20130301 3

Angiogenesis requires coordinated dynamic regulation of multiple phenotypic behaviors of endothelial cells in response to environmental cues. Multi-scale computational models of angiogenesis can be useful for analyzing effects of cell behaviors on the tissue level outcome, but these models require more intensive experimental studies dedicated to determining the required quantitative "rules" for cell-level phenotypic responses across a landscape of pro- and anti-angiogenic stimuli in order to asc ...[more]

PMID: 23303249

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Project description:The skeletal muscle tissue can adapt to exercise and environmental stressors with a remarkable plasticity. Prolonged cold stress exposure has been associated to increased skeletal muscle capillarization. Angioadaptation refers to the coordinated molecular and cellular processes that influence the remodeling of skeletal muscle microvasculature. Two cell types are central to angioadaptation: the myocytes, representing an important source of angiokines; and the skeletal muscle endothelial cell (SMECs), targets of these angiokines and main constituents of muscle capillaries. The influence of cold stress on skeletal muscle angioadaptation remains largely unknown, particularly with respect to myocyte-specific angiokines secretion or endothelial cell angioadaptive responses. Here, we use an in vitro model to investigate the impact of cold stress (28°C versus 37°C) on C2C12 myotubes and SMECs. Our main objectives were to evaluate: 1) the direct impact of cold stress on C2C12 cellular expression of angiokines and their release in the extracellular environment; 2) the indirect impact of cold stress on SMECs migration via these C2C12-derived angiokines; and 3) the direct effect of cold stress on SMECs angioadaptive responses, including migration, proliferation, and the activation of the vascular endothelial growth factor receptor-2 (VEGFR2). Cold stress reduced the secretion of angiokines in C2C12 myotubes culture media irrespective their pro-angiogenic or angiostatic nature. In SMECs, cold stress abrogated cell proliferation and reduced the activation of VEGFR2 despite a greater expression of this receptor. Finally, SMECs pre-conditioned to cold stress displayed an enhanced migratory response when migration was stimulated in rewarming conditions. Altogether our results suggest that cold stress may be overall angiostatic. However, cold stress accompanied by rewarming may be seen as a pro-angiogenic stressor for SMECs. This observation questions the potential for using pre-cooling in sport-performance or therapeutic exercise prescription to enhance skeletal muscle angioadaptive responses to exercise.

Dataset Information

Endothelial cell phenotypic behaviors cluster into dynamic state transition programs modulated by angiogenic and angiostatic cytokines.

Publications

Endothelial cell phenotypic behaviors cluster into dynamic state transition programs modulated by angiogenic and angiostatic cytokines.

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