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Mechanical forces are key modulators of valvulogenic developmental programs. However, the mechanosensitive gene network underlying this process remains unclear. It is well established that contractile and flow forces activate endocardial expression of the transcription factorklf2aduring valve morphogenesis. We report two novel transcription factors with a function in heart valve formation in zebrafish:egr1andklf2b. Genome-wide analysis of gene expression reveals that the endocardial transcriptional programs modulated byklf2a,klf2b, andegr1mainly contain non-redundant targets. Several of these targets have been implicated in endothelial-to-mesenchymal transition (EMT). Many of the deregulated genes exhibit changes in chromatin accessibility pointing to potential direct effects of these factors. Finally,in vivophenotypic analyses show that VEGF receptor 1 (flt1)is a target ofegr1andklf2bduring early valvulogenesis. These findings suggest thatklf2a,klf2b, andegr1cooperate for the activation of EMT program in response to mechanosensitive inputs. We propose that the combinatorial action of these factors mediates flow mechanotransduction to control the endocardial program, especially for valve development.