Mechanical stretch, an important growth stimulus, results not only from pulsatile blood flow and diastolic stretch of the ventricles (cyclic stretch, CS), but also from tissue expansion during growth (constant static stretch, SS). We compared growth factor receptor expression and vasculogenic/angiogenic responses of rat coronary microvascular endothelial cells (RCMEC) by exposing the cells to CS (10% elongation at 30 cycles/min) and SS (a constant 10% elongation). Both CS and SS increased VEGF-R2 protein levels and the extent of tube formation and branching. Moreover, both CS and SS enhanced VEGF-induced cell proliferation and tube formation indicating that both types of stretch increase sensitivity of EC to VEGF. Blockade of VEGF-R2 prevented the increases in endothelial cell proliferation and aggregate tube length. However, CS but not SS, enhanced EC Tie-2 protein and migration. CS affected a greater increase in tube length and branch formation than did SS. A unique finding was that SS, but not CS increased VEGFR-1 EC. Our study is the first to distinguish between the effects of CS and SS on growth factor receptor expression and RCMEC proliferation, migration, and tube formation. Conclusion: endothelial cell angiogenic responses to these two types of stretch display both differences and similarities, but both CS and SS are dependent on VEGF-R2 signaling for their vasculogenic/angiogenic effects.