Angiogenesis is an important feature of airway remodeling in both chronic asthma and COPD. Airways in those conditions are exposed to excessive mechanical strain during periods of acute exacerbations. We recently reported that mechanical strain of human airway smooth muscle (HASM) led to an increase in their proliferation and migration. Sustained growth in airway smooth muscle in vivo requires angiogenesis. In this study we examined the hypothesis that cyclic mechanical strain of human airway smooth muscle produces factors promoting angiogenic events in the surrounding vascular endothelial cells. Our results show that: 1) A significant increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, migration and tube formation following incubation in conditioned media (CM) from HASM cells exposed to mechanical strain; 2) Mechanical strain of HASM cells induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited the proliferation, migration and tube formations of HMVEC-L induced by the strained airway smooth muscle CM; 4) Mechanical strain of HASM induced a significant increase in hypoxia inducible factor-1 (HIF-1 ) mRNA and protein, a transcription factor required for VEGF gene transcription, and 5) Mechanical strain of HASM induced HIF-1 /VEGF through dual PI3K/Akt/mTOR and ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces signal transduction pathway through PI3 kinase/Akt/ mTOR and ERK pathways that lead to an increase in HIF-1 , a transcription factor required for VEGF expression. VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen with repeated exacerbation of asthma and COPD.