Bone morphogenetic protein (BMP)-9 enhances high glucose-mediated microvascular damage

Bone morphogenetic protein (BMP)-9, a member of the TGF-β superfamily of cytokines is produced in the liver. Culturing hepatic stellate cells (HSC) under conditions of high glucose was reported to enhance HSC activation in vitro. Using real-time PCR we now found that such culture-conditions also lead to significantly enhanced expression of BMP-9. Since BMP-9 is a secreted cytokine, circulating with the blood stream this observation led us to investigate possible consequences of glucose-mediated elevation of BMP-9 levels on endothelial cells. In macrovascular endothelial cells (HUVEC) as well as liver sinusoidal endothelial cells (LSEC) and primary mouse hepatocytes, BMP-9 stimulation induced an upregulation of VEGF expression as determined by real-time PCR. In LSEC as well as brain microvascular endothelial cells BMP-9 induced expression of capillarization markers like fibronectin and Integrins αv and β3. In line with this observation, we found by immunohistochemistry a deposition of fibronectin within the sinusoids of diabetic mouse livers. These data suggest that systemic elevations of BMP-9 levels occur under hyperglycaemic conditions and that BMP-9 aggravates high-glucose-mediated microvascular damage. These findings further imply that application of BMP-9 neutralizing agents might be a promising new strategy to protect patients from diabetes-induced microvascular damage in the future.