SHP2mediates the activities of multiple receptor tyrosine kinase signaling and itsfunction in endothelial processes has been explored extensively. However,genetic studies on the role of SHP2 in tumor angiogenesis have not beenconducted. Here, we show that SHP2 is activated in tumor endothelia. Shp2 deletion and pharmacological inhibition reduce tumor growth and microvasculardensity in multiple mouse tumor models. Shp2 deletion also leads to tumorvascular normalization, indicated by increased pericyte coverage and vesselperfusion. SHP2 inefficiency impairs endothelial cell proliferation, migration,and tubulogenesis through downregulating the expression of proangiogenicSRY-Box transcription factor 7 (SOX7), whose re-expression restores endothelialfunction in SHP2-knockdown cells and tumor growth, angiogenesis, and vascularabnormalization in Shp2-deleted mice. SHP2 stabilizes apoptosissignal-regulating kinase 1 (ASK1), which regulates SOX7 expression mediated byc-Jun. Our studies suggest SHP2 in tumor associated endothelial cells is apromising anti-angiogenic target for cancer therapy.