Based on studies in mouse, NOTCH3 intracellular domain (NICD3), likely in complex with RBPJ and MAML (MAML1, MAML2 or MAML3), positively regulates transcription from the HES5 gene promoter. While HES5 promoter contains RBPJ binding elements, direct binding of the NOTCH3 coactivator complex to the HES5 promoter has not been demonstrated (Lin et al. 2002, Shimizu et al. 2002). Studies in rats suggest that NOTCH3-mediated upregulation of HES5 plays a key role in the development of pulmonary arterial hypertension. NOTCH3 and HES5 are both expressed in vascular smooth muscle cells of small pulmonary arteries of human and rat lungs, with NOTCH3 and HES5 levels increased in hypertensive human and rat lung tissues (Li et al. 2009).