BMP9/COX‐2 axial mediates high phosphate‐induced calcification in vascular smooth muscle cells via Wnt/β‐catenin pathway

Abstract

Vascular calcification is a notable risk factor for cardiovascular system. High phosphate can induce calcification in vascular smooth muscle cells (VSMCs), but the detail mechanism underlying this process remains unclear. In the present study, we determined the relationship between high phosphate and bone morphogenetic protein 9 (BMP9) in VSMCs, the effect of BMP9 on calcification in VSMCs and the effect of COX-2 on BMP9 induced calcification in VSMCs, as well as the possible mechanism underlying this biological process. We found that high phosphate obviously up-regulates the expression of BMP9 in VSMCs. Over-expression of BMP9 decreases the level of alpha-smooth muscle cell actin (α-SMA) apparently, but increases the level of Runx-2, Dlx-5, and ALP in VSMCs. Meanwhile, BMP9 increases the level of OPN and OCN, promotes mineralization in VSMCs and induces calcification in thoracic aorta. High phosphate and over-expression of BMP9 increases the level of COX-2. Over-expression of COX-2 enhances the inhibitory effect of BMP9 on α-SAM and increases the level of OPN and OCN induced by BMP9. However, inhibition of COX-2 decreases the BMP9-induced calcification in VSMCs and thoracic aorta. For mechanism, we found that high phosphate or BMP9 increases the level of β-catenin and p-GSK3β in VSMCs, but no substantial effect on GSK3β. However, COX-2 inhibitor decreases the expression of β-catenin induced by BMP9. Our findings indicated that BMP9 is involved in the phosphate-induced calcification in VSMCs and COX-2 partly mediates the BMP9-induced calcification in VSMCs through activating Wnt/β-catenin pathway.

Vascular calcification is associated with Wnt‐signaling pathway and blood pressure variability in chronic kidney disease rats

“…Our study indicated that Wnt pathway was involved in CKD VC, which is consistent with previous studies . Addition of Wnt pathway inhibitor secreted frizzeled‐related protein 5 could inhibit high phosphate‐induced calcification of VSMCs .…”

Klotho/FGF23 axis mediates high phosphate‐induced vascular calcification in vascular smooth muscle cells via Wnt7b/β‐catenin pathway

“… Besides, Rong et al reported that BMP‐2 plays a crucial role both in calcium deposition in VSMCs and VC in CKD patients via a mechanism involving the Wnt/β‐catenin pathway . In addition, BMP‐9 was also been reported to induce VC through activating the Wnt/β‐catenin pathway . In contrast, Deng et al revealed secreted frizzled‐related protein 5 (SFRP5) attenuates high phosphate‐induced calcification in vascular smooth muscle cells by inhibiting the Wnt/β‐catenin pathway .…”

“…Primary rat aortic VSMCs were employed for this study. The primary rat aortic VSMCs were extracted and cultured as described . Briefly, Male Sprague‐Dawley (SD) rats (150‐180 g, 10‐12 week) were ordered from the Laboratory Animal Center of Chongqing Medical University.…”

“…The primary rat aortic VSMCs were extracted and cultured as described. 6 Briefly, Male Sprague-Dawley (SD) rats (150-180 g, 10-12 week) were ordered from the Laboratory Animal Center of Chongqing Medical University. All animal experiments were approved by the institutional animal care and use committee (IACUC).…”

“…Vascular calcification (VC) is very common and, at present, it is one of the main complications of CKD, which increases the CVD related mortality. 5,6 The formation of VC is associated with complex pathological mechanisms, including osteochondral differentiation and apoptosis of vascular smooth muscle cells (VSMCs), instability and release of extracellular vesicles loaded calcium and phosphate. 1,7 Among the various causes in CKD, abnormal deposition of calcium phosphate (Pi) salt is most closely related to VC.…”