Module-based multiscale simulation of angiogenesis in skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Mathematical modeling of angiogenesis has been gaining momentum as a means to shed new light on the biological complexity underlying blood vessel growth. A variety of computational models have been developed, each focusing on different aspects of the angiogenesis process and occurring at different biological scales, ranging from the molecular to the tissue levels. Integration of models at different scales is a challenging and currently unsolved problem.</p> <p>Results</p> <p>We present an object-oriented module-based computational integration strategy to build a multiscale model of angiogenesis that links currently available models. As an example case, we use this approach to integrate modules representing microvascular blood flow, oxygen transport, vascular endothelial growth factor transport and endothelial cell behavior (sensing, migration and proliferation). Modeling methodologies in these modules include algebraic equations, partial differential equations and agent-based models with complex logical rules. We apply this integrated model to simulate exercise-induced angiogenesis in skeletal muscle. The simulation results compare capillary growth patterns between different exercise conditions for a single bout of exercise. Results demonstrate how the computational infrastructure can effectively integrate multiple modules by coordinating their connectivity and data exchange. Model parameterization offers simulation flexibility and a platform for performing sensitivity analysis.</p> <p>Conclusions</p> <p>This systems biology strategy can be applied to larger scale integration of computational models of angiogenesis in skeletal muscle, or other complex processes in other tissues under physiological and pathological conditions.</p

Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis which drives endothelial cell survival, proliferation, and migration while increasing vascular permeability. Playing an important role in the physiology of normal ovaries, VEGF has also been implicated in the pathogenesis of ovarian cancer. Essentially by promoting tumor angiogenesis and enhancing vascular permeability, VEGF contributes to the development of peritoneal carcinomatosis associated with malignant ascites formation, the characteristic feature of advanced ovarian cancer at diagnosis. In both experimental and clinical studies, VEGF levels have been inversely correlated with survival. Moreover, VEGF inhibition has been shown to inhibit tumor growth and ascites production and to suppress tumor invasion and metastasis. These findings have laid the basis for the clinical evaluation of agents targeting VEGF signaling pathway in patients with ovarian cancer. In this review, we will focus on VEGF involvement in the pathophysiology of ovarian cancer and its contribution to the disease progression and dissemination

Matrix metalloproteinase 9 opposes diet-induced muscle insulin resistance in mice

AIMS/HYPOTHESIS: Increased extracellular matrix (ECM) collagen is a characteristic of muscle insulin resistance. MMP9 is a primary enzyme that degrades collagen IV (ColIV). As a component of the basement membrane, ColIV plays a key role in ECM remodeling. The hypotheses that genetic deletion of MMP9 in mice 1) increases muscle ColIV, 2) induces insulin resistance in lean mice, and 3) worsens diet-induced muscle insulin resistance were tested. METHODS: Wild type (mmp9(+/+)) and MMP9 null (mmp9(−/−)) mice were chow or high fat (HF) fed for 16wks. Insulin action was measured by the hyperinsulinemic, euglycemic clamp in conscious weight-matched surgically catheterized mice. RESULTS: mmp9(−/−) and HF feeding independently increased muscle ColIV. ColIV in HF-fed mmp9(−/−) was further increased. mmp9(−/−) did not affect fasting insulin or glucose in chow- or HF-fed mice. Glucose infusion rate (GIR), endogenous glucose appearance (EndoRa) and glucose disappearance (Rd) rates, and a muscle glucose metabolic index (Rg) were the same in chow-fed mmp9(+/+) and mmp9(−/−). In contrast, HF-fed mmp9(−/−) decreased GIR, insulin-stimulated increase in Rd, and muscle Rg. Insulin-stimulated suppression of EndoRa was however, remained the same between HF-fed mmp9(−/−) and mmp9(+/+). Decreased muscle Rg in HF-fed mmp9(−/−) was associated with decreased muscle capillaries. CONCLUSION/INTERPRETATION: Despite increased muscle ColIV, genetic deletion of MMP9 does not induce insulin resistance in lean mice. In contrast, it results in a more profound insulin resistant state, specifically in skeletal muscle in HF-fed mice. These results highlight the importance of ECM remodeling in determining muscle insulin resistance in the presence of HF diet