A hypertension patient derived induced pluripotent stem cell model demonstrates a role for GPER in hypertension risk and development

Hypertension (HTN) is a polyfactorial disease that can manifest severe cardiovascular pathologies such as heart failure or stroke. Genome Wide Association Studies (GWAS) of HTN indicate that single nucleotide polymorphisms (SNPs) contribute to increased risk for HTN and resistance to some HTN drug regimens (19, 26, 35, 52). However, cellular mechanistic insights of such SNPs remain largely unknown. Using a HTN patient-derived induced pluripotent stem cell (iPSC) bank and CRISPR/Cas9-mediated gene editing approach, we investigated the effects of a female HTN risk-associated SNP (rs1154431) of the G protein-coupled estrogen receptor (GPER) (5) in vascular endothelial cells. Although GPER deletion reduced eNOS activation in iPSC-derived endothelial cells (iEC), the polymorphism itself did not significantly affect eNOS and NO production in a comparison of isogenic hemizygous iECs expressing either normal (P16) or HTN-associated (L16) GPER. Interestingly, we demonstrate for the first time that GPER plays a role in regulation of adhesion molecule expression and monocyte adhesion to iECs. Moreover, the L16 iECs had higher expression of inflammation genes over P16 iECs, implying that the risk variant may affect carrier individuals through increased inflammatory activity. This study further indicates that iPSC are a useful platform for exploring mechanistic insights underlying hypertension GWAS endeavors.