Background and Aims: Somatostatin is a peptide hormone that regulates the release of several other endocrine hormones and affects neurotransmission and cell proliferation by activation of one or more of five well-known G protein-coupled somatostatin receptors (SSTR1-5). Although, its endocrine regulatory and anti-tumour effects are well studied, little is known about its effect on vascular system. The aim of the present study was to analyse the effects of somatostatin on endothelial barrier function and angiogenesis in vitro. Methods: The study was carried out on cultured human umbilical vein endothelial cells (HUVEC). EC barrier function was analysed by measuring flux of albumen through EC monolayers cultured on filter membranes. Angiogenesis was analysed by endothelial cell migration (wound assay), 3-D tubes and spheroid formation. Somatostatin-14 (10-100 pM) synthetic peptide was used to specifically activate somatostatin receptors. Results: Quantitative PCR data suggested that HUVEC express somatostatin receptors 4 and 5. Treatment of EC monolayers with somatostatin (24h) sensitized endothelial monolayer to thrombin-induced hyperpermeability in a concentration-dependent (10pM-1nM) manner. The Western blot data demonstrated that somatostatin caused an activation of p42/44 MAPK and pharmacological inhibition of MAPK abrogated the barrier sensitizing effects of somatostatin. Similarly, treatment of ECs with somatostatin potentiated pro-proliferative and pro-angiogenic effects of VEGF which were also abrogated by pharmacological inhibition of MAPK. Conclusion: The data of present study demonstrate that long-term treatment of ECs with somatostatin sensitizes endothelial monolayer towards thrombin-induced endothelial hyperpermeability and enhance the angiogenic effects of VEGF. The pro-angiogenic property of somatostatin can be exploited to enhance cardiac recovery in ischemic injury.