ABSTRACT: AIMS:Activation of vascular GPER has been linked to vasodepressor effects in animals. However, the significance of GPER regulation on chronic blood pressure control in humans is unknown. METHODS:To examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16L in vascular smooth muscle cells, and its association with blood pressure in humans. Further, to validate the importance of carrying GPER P16L in the development of hypertension we assessed allele frequency in a cohort of hard-to-treat hypertensive patients referred to a tertiary care clinic. RESULTS:Expression of the GPER P16L variant (V) vs. wild type (WT) in rat aortic vascular smooth muscle cells, was associated with a significant decrease in G1 (1??m, a GPER agonist)-mediated ERK phosphorylation (slope of the function of G1-stimulated ERK phosphorylation: GPER content WT: 16.2, 95% CI 9.9, 22.6; V: 5.0, 95% CI 1.0, 9.0; P < 0.005) and apoptosis (slope of the function of G1-stimulated apoptosis: GPER content: WT: 4.4, 95% CI: 3.4, 5.4; V: 2.5, 95% CI 1.6, 2.3 P < 0.005). Normotensive female subjects, but not male subjects, carrying this hypofunctional variant (allele frequency 22%) have increased blood pressure [mean arterial pressure: P16/P16: 80 ± 1?mmHg (n = 204) vs.?P16L carriers: 82 ± 1?mmHg (n = 127), 95% CI for difference: 0.6, 4.0?mmHg, P < 0.05], [systolic blood pressure: P16/P16: 105 ± 1?mmHg vs. P16L carriers: 108 ± 1?mmHg, 95% CI for difference:1.0, 5.1?mmHg, P < 0.05], [diastolic blood pressure: P16/P16: 66 ± 0.5?mmHg vs. P16L carriers 68 ± 0.7, 95% CI for difference: 0.2, 3.6?mmHg, P < 0.05]. Further, the P16L allele frequency was almost two-fold higher in female vs. male hypertensive patients (31% vs. 16%, allele ratio 0.5, 95% CI 0.32, 0.76, P < 0.05). CONCLUSIONS:The common genetic variant, GPER P16L, is hypofunctional and female carriers of this allele have increased blood pressure. There was an increased prevalence in a population of hard-to-treat hypertensive female patients. Cumulatively, these data suggest that in females, impaired GPER function might be associated with increased blood pressure and risk of hypertension.
