Protective role of endothelial progenitor cells stimulated by riociguat in chronic thromboembolic pulmonary hypertension

Abstract

Background: Pulmonary endothelial damage has a negative impact on the maintenance of normal pulmonary vascular function. Such damage results in delayed thrombus dissolution and vascular remodeling in chronic thromboembolic pulmonary hypertension (CTEPH). Although endothelial progenitor cells (EPCs) may be incorporated into neovasculature during vascular repair, their function in CTEPH remains unclarified, especially under the augmentation of soluble guanylate cyclase (sGC) activity. Methods and results: We evaluated the effect of EPCs on endothelial function and compared the effect of riociguat, a sGC stimulator, on the number and function of circulating EPCs in two groups of CTEPH patients. The two groups consisted 16 CTEPH patients who were treatment naïve (Naïve group), and 14 CTEPH patients who were being treated with riociguat, a sGC stimulator (Riociguat group). The number of circulating EPCs in the Riociguat group was significantly higher than that in the Naïve group. Gene expression levels associated with angiogenesis were significantly higher in EPCs of the Riociguat group. EPC-stimulated tube formation and migration of human pulmonary microvascular endothelial cell (hPMVEC) in the Riociguat group exceeded that in the Naïve group. The angiogenic ability of hPMVECs stimulated by EPCs in the Riociguat group was enhanced compared to that of the sGC stimulator, BAY 41-2272. Conclusion:These findings indicate that riociguat may induce EPCs to play a protective role via modulation of endothelial functions associated with CTEPH. Translation aspect of the work: Endothelial dysfunction exacerbates CTEPH. Riociguat enhanced the protective role of EPCs via neovascularization, which prevented vascular remodeling and alleviated CTEPH.

Riociguat inhibits ultra‐large VWF string formation on pulmonary artery endothelial cells from chronic thromboembolic pulmonary hypertension patients

“…VWF expression and secretion into the circulation can be regulated via various transcriptional and (post)translational mechanisms 27 . Although recent data from our group has shown that VWF expression in PAECs from CTEPH patients is regulated on the transcriptional level under inflammatory conditions, 21 and that previous studies showed that mRNA levels of VWF were decreased in endothelial progenitor cells from patients receiving riociguat, 28 we were not able to observe an anti‐inflammatory effect that reduced VWF mRNA expression in PAEC after in vitro riociguat stimulation. From these results, we considered that the suppressed VWF strings formation was unrelated to VWF expression.…”

Stem cell therapy in pulmonary hypertension: current practice and future opportunities

“…In EPC regulation therapy, riociguat has been proposed as a potential therapeutic intervention for PH [127]. A study conducted by YAMAMOTO et al [61] investigated the effects of riociguat on PH-related parameters and its potential mechanism of action. The results showed that the riociguat group did not exhibit significant improvements in terms of demographic and haemodynamic parameters, oxygenation or the 6-MWD compared to the naïve group.…”

The achievements of the modern specific therapy of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: focus on the stimulator of soluble guanylate cyclase riociguat

“…Эти результаты указывают на то, что риоцигуат может индуцировать продукцию клетокпредшественников эндотелия, выполняя защитную роль через модуляцию эндотелиальных функций, связанных с ХТЭЛГ. Полученные результаты требуют изучения в дальнейших исследованиях [25].…”