Insulin Resistance Impairs Circulating Angiogenic Progenitor Cell Function and Delays Endothelial Regeneration

OBJECTIVE Circulating angiogenic progenitor cells (APCs) participate in endothelial repair after arterial injury. Type 2 diabetes is associated with fewer circulating APCs, APC dysfunction, and impaired endothelial repair. We set out to determine whether insulin resistance adversely affects APCs and endothelial regeneration. RESEARCH DESIGN AND METHODS We quantified APCs and assessed APC mobilization and function in mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. Endothelial regeneration after femoral artery wire injury was also quantified after APC transfusion. RESULTS IRKO mice, although glucose tolerant, had fewer circulating Sca-1+/Flk-1+ APCs than WT mice. Culture of mononuclear cells demonstrated that IRKO mice had fewer APCs in peripheral blood, but not in bone marrow or spleen, suggestive of a mobilization defect. Defective vascular endothelial growth factor–stimulated APC mobilization was confirmed in IRKO mice, consistent with reduced endothelial nitric oxide synthase (eNOS) expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of APCs from IRKO mice was impaired compared with those from WT animals. Endothelial regeneration of the femoral artery after denuding wire injury was delayed in IRKO mice compared with WT. Transfusion of mononuclear cells from WT mice normalized the impaired endothelial regeneration in IRKO mice. Transfusion of c-kit+ bone marrow cells from WT mice also restored endothelial regeneration in IRKO mice. However, transfusion of c-kit+ cells from IRKO mice was less effective at improving endothelial repair. CONCLUSIONS Insulin resistance impairs APC function and delays endothelial regeneration after arterial injury. These findings support the hypothesis that insulin resistance per se is sufficient to jeopardize endogenous vascular repair. Defective endothelial repair may be normalized by transfusion of APCs from insulin-sensitive animals but not from insulin-resistant animals

Climate change and habitat fragmentation drive the occurrence of Borrelia burgdorferi, the agent of Lyme disease, at the northeastern limit of its distribution

Lyme borreliosis is rapidly emerging in Canada, and climate change is likely a key driver of the northern spread of the disease in North America. We used field and modeling approaches to predict the risk of occurrence of Borrelia burgdorferi, the bacteria causing Lyme disease in North America. We combined climatic and landscape variables to model the current and future (2050) potential distribution of the black-legged tick and the white-footed mouse at the northeastern range limit of Lyme disease and estimated a risk index for B. burgdorferi from these distributions. The risk index was mostly constrained by the distribution of the white-footed mouse, driven by winter climatic conditions. The next factor contributing to the risk index was the distribution of the black-legged tick, estimated from the temperature. Landscape variables such as forest habitat and connectivity contributed little to the risk index. We predict a further northern expansion of B. burgdorferi of approximately 250-500 km by 2050 - a rate of 3.5-11 km per year - and identify areas of rapid rise in the risk of occurrence of B. burgdorferi. Our results will improve understanding of the spread of Lyme disease and inform management strategies at the most northern limit of its distribution.Julie A. Simon, Robby R. Marrotte, Nathalie Desrosiers, Jessica Fiset, Jorge Gaitan, Andrew Gonzalez, Jules K. Koffi, Francois-Joseph Lapointe, Patrick A. Leighton, Lindsay R. Lindsay, Travis Logan, Francois Milord, Nicholas H. Ogden, Anita Rogic, Emilie Roy-Dufresne, Daniel Suter, Nathalie Tessier, and Virginie Millie

Prostaglandin E2 Promotes Endothelial Differentiation from Bone Marrow-Derived Cells through AMPK Activation

Prostaglandin E2 (PGE2) has been reported to modulate angiogenesis, the process of new blood vessel formation, by promoting proliferation, migration and tube formation of endothelial cells. Endothelial progenitor cells are known as a subset of circulating bone marrow mononuclear cells that have the capacity to differentiate into endothelial cells. However, the mechanism underlying the stimulatory effects of PGE2 and its specific receptors on bone marrow-derived cells (BMCs) in angiogenesis has not been fully characterized. Treatment with PGE2 significantly increased the differentiation and migration of BMCs. Also, the markers of differentiation to endothelial cells, CD31 and von Willebrand factor, and the genes associated with migration, matrix metalloproteinases 2 and 9, were significantly upregulated. This upregulation was abolished by dominant-negative AMP-activated protein kinase (AMPK) and AMPK inhibitor but not protein kinase, a inhibitor. As a functional consequence of differentiation and migration, the tube formation of BMCs was reinforced. Along with altered BMCs functions, phosphorylation and activation of AMPK and endothelial nitric oxide synthase, the target of activated AMPK, were both increased which could be blocked by EP4 blocking peptide and simulated by the agonist of EP4 but not EP1, EP2 or EP3. The pro-angiogenic role of PGE2 could be repressed by EP4 blocking peptide and retarded in EP4+/− mice. Therefore, by promoting the differentiation and migration of BMCs, PGE2 reinforced their neovascularization by binding to the receptor of EP4 in an AMPK-dependent manner. PGE2 may have clinical value in ischemic heart disease

The influence of habitat and landscape structure on the genetic differentiation of the white-footed mouse (Peromyscus leucopus)

The white-footed mouse (Peromyscus leucopus) is a widespread habitat generalist species abundant over a large part of the North-American continent. In the past decade, due to climate and land use change, the range of this species has expanded northwards into Canada. The black-legged tick (Ixodes scapularis), is the vector of Lyme disease which also has tracked climate change over the last few decades. This may have been further promoted by the growing presence of P. leucopus, a favored host for the tick. Therefore, aspects of the landscape that affect the movement and distribution of the white-footed mouse, will also affect the expansion of the tick, and consequently the spread of Lyme disease. In this thesis, I first reviewed published results that relied on genetic and non- genetic biological data to investigate the influence of local habitat and landscape characteristics on the movement and dispersal patterns in the white footed-mouse. Next, I evaluated the relations between breeding habitat and landscape resistance against the genetic differentiation between 11 populations in Montérégie, Québec, Canada. I was able to simultaneously measure the effect of the habitat and the landscape on the genetic differentiation of these mouse populations by utilizing numerical optimization to fit a model to previously published genetic data. I used ecological distance computed from resistance surfaces with Circuitscape to infer the effect of the landscape. Concurrently, I estimated the habitat quality of our sampling localities and correlated these to relevant habitat measurements. I found that both characteristics within and between forest patches have more of an impact on genetic differentiation than the geographical distance between the mice populations. This suggests that this species can disperse and use a wide range of habitats, in accordance with its recent rapid expansion in the region.La souris à pattes blanches (Peromyscus leucopus) est une espèce généraliste à large distribution sur le continent Nord-américain. En relation avec le réchauffement climatique et les changements dans l'utilisation des terres, cette espèce étend sa distribution vers le nord au Canada. La tique à pattes noires (Ixodes scapulatis), vecteur de la maladie de Lyme, a aussi suivi le changement climatique par un déplacement de la limite nord de sa distribution au Canada. Cette expansion vers le nord pourrait avoir été favorisée par la présence croissante de P. leucopus, un hôte préférentiel pour la tique. Les aspects du paysage qui affectent le mouvement et la distribution de la souris à pattes blanches, affecteront ainsi l'expansion de la tique et par conséquent, de la maladie de Lyme. Dans ce mémoire, j'ai d'abord effectué une revue de publications qui ont examiné l'influence de caractéristiques d'habitat locales et du paysage sur le mouvement et la dispersion de la souris à pattes blanches. Ensuite, j'ai évalué l'influence de caractéristiques de l'habitat et du paysage sur la différenciation génétique entre des populations situées en Montérégie, Québec, Canada. J'ai pu mesurer simultanément l'effet de l'habitat et du paysage sur la différenciation génétique de 11 populations de souris en utilisant une optimisation numérique. J'ai utilisé des distances écologiques calculées à partir de surfaces de résistance avec Circuitscape pour déduire l'effet du paysage. En parallèle, j'ai estimé la qualité de l'habitat de sites d'échantillonnage et corrélé cet index aux mesures d'habitat prises sur le terrain. J'ai trouvé que les caractéristiques dans et entre les patches forestiers ont plus d'impact sur la différenciation génétique que la distance géographique. Ceci suggère que cette espèce peut disperser et utiliser une vaste gamme d'habitats, conformément à son expansion rapide récente dans la région

The relationship between least-cost and resistance distance

<div><p>Least-cost modelling and circuit theory are common analogs used in ecology and evolution to model gene flow or animal movement across landscapes. Least-cost modelling estimates the least-cost distance, whereas circuit theory estimates resistance distance. The bias added in choosing one method over the other has not been well documented. We designed an experiment to test whether both methods were linearly related. We also tested the sensitivity of these metrics to variation in Euclidean distance, spatial autocorrelation, the number of pixels representing the landscape, and data aggregation. We found that least-cost and resistance distance were not linearly related unless a transformation was applied. Resistance distance was less sensitive to the number of pixels representing a landscape and was also less sensitive than least-cost distance to the Euclidean distance between nodes. Spatial autocorrelation did not affect either method or the relationship between methods. Resistance distance was more sensitive to aggregation in any form compared to least-cost distance. Therefore, the metric used to infer movement or gene flow and the manipulations applied to the data used to calculate these metrics may govern findings.</p></div

Data from: Landscape resistance and habitat combine to provide an optimal model of genetic structure and connectivity at the range margin of a small mammal

We evaluated the effect of habitat and landscape characteristics on the population genetic structure of the white-footed mouse. We develop a new approach that uses numerical optimization to define a model that combines site differences and landscape resistance to explain the genetic differentiation between mouse populations inhabiting forest patches in southern Québec. We used ecological distance computed from resistance surfaces with Circuitscape to infer the effect of the landscape matrix on gene flow. We calculated site differences using a site index of habitat characteristics. A model that combined site differences and resistance distances explained a high proportion of the variance in genetic differentiation and outperformed models that used geographical distance alone. Urban and agriculture related land uses were, respectively, the most and the least resistant landscape features influencing gene flow. Our method detected the effect of rivers and highways as highly resistant linear barriers. The density of grass and shrubs on the ground best explained the variation in the site index of habitat characteristics. Our model indicates that movement of white-footed mouse in this region is constrained along routes of low resistance. Our approach can generate models that may improve predictions of future northward range expansion of this small mammal

The use of least-cost modelling and circuit theory in ecology.

<p>Cumulative increase in the number of Google Scholar articles that have mentioned Circuitscape and least-cost modelling in the field of Ecology since 2000.</p