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Long-term blockade of nitric oxide synthesis with Nω-nitro-L-arginine methyl ester (L-NAME) induces cardiac perivascular fibrosis in rats. Its relationship to expression of angiogenic growth factors and capillary network remodeling is not understood. This study was designed to determine whether capillary proliferation and angiogenic growth factor regulation occur in response to L-NAME. Three groups of rats were studied: C, control; L1, L-NAME 13 mg/kg/day; L2, 130 mg/kg/day. One and eight weeks later the hearts were removed and subjected to morphometric analysis and analysis of gene expressions of molecules related to angiogenesis. Arterial hypertension was observed within 8 weeks in the L1 and L2 groups compared with control. After 1 week immunohistochemical assays demonstrated basic fibroblast growth factor (bFGF) in the arteriolar media. Northern blot analysis revealed increase in bFGF and transforming growth factor-β (TGF-β) mRNA during this period. At 8 weeks arteriolar medial thickening and perivascular fibrosis were seen microscopically in the L1 and L2 groups, which were accompanied by only a modest remodeling of capillary network due to increase in venular or intermediate capillary portions. Concomitantly immunoreactivity for vascular endothelial growth factor (VEGF) and TGF-β were detected in perivascular area. These results suggest that (1) blockade of NO synthesis induces expression of angiogenic growth factors as well as vessel wall remodeling, and (2) TGF-β may counteract angiogenic growth factors and limit subsequent alterations in capillary network remodeling. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomarkers are currently being developed. Specifically, next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use-including proof-of-mechanism, patient selection, assessment of treatment efficacy and safety rates, and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD "signatures" through multifactorial and interindividual variability, allowing us to decipher disease pathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs.
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