Gene expression changes evoked in a venous segment exposed to arterial flow

Objective: This study was conducted to characterize the coordinated molecular changes evoked in the structure and composition of the wall of a venous segment when exposed to fistula flow. Methods: An arteriovenous shunt was created in adult C57BL/6J mice. Remodeled veins and contralateral control jugular veins were isolated 7 days after surgery. Total RNA was isolated, linearly amplified, and the transcriptional profiles of this early adaptive response were obtained by microarray analysis. Histologic and immunohistochemical analyses were performed on remodeled veins and control veins isolated on days 1, 3, 5, and 7 after surgery to further examine distinct spatial and temporal aspects of this early process. Results: There were 131 significantly upregulated and 165 downregulated genes in the remodeled vein compared with the control jugular vein. Genes involved in extracellular matrix reorganization were highly upregulated. Movat's pentachrome staining revealed ground substance on day 3 that was not observed on day 5. The appearance of elastin fibers was first observed on day 7. Morphometric analysis demonstrated maximum wall thickness on day 3. Immunohistochemical analysis revealed the presence of tenascin-C, thrombospondin, lysyl oxidase, and osteopontin in different cell types at different time points throughout the first week after surgery. Conclusion: Major changes in the organization of the extracellular matrix occur during the early response of venous remodeling. Elastin, tenascin-C, thrombospondin, lysyl oxidase, and osteopontin are expressed within the wall of the remodeling vein resulting in the de novo formation of an extracellular matrix scaffold that may be part of a critical adaptation program being evoked to allow the vessel to cope with its new biomechanical environment.