Communication can take place via direct cellular or via paracrine interactions induced by secretion of molecules such as platelet-derived growth factor. With regard to the endothelium��s crucial role for the Epimedin-C maintenance of the integrity of the vascular wall, we decided to concentrate our studies on endothelial cells to elucidate the pathogenesis of Loeys-Dietz syndrome. Recently, several studies revealed a direct link between TGF-b and Gremlin-1 signalling. Interestingly, although the majority of TGF-b receptor mutations in LDS patients results in nonfunctional receptor kinase activity, increased phosphorylation levels of the TGF-b downstream mediator proteins SMAD2 and SMAD3 have been observed in the aortic tissue of LDS patients. In concordance with these observations, the expression of a kinase-deficient TGFBR2 variant in a transgenic mouse model resulted in TGF-b overactivity including increased SMAD2/3 phosphorylation and induced development of fibrosis. Several recently published studies could directly link TGF-b-induced phosphorylation of SMAD2/3 to increased Gremlin-1 expression. Hence, elevated Gremlin-1 expression levels might represent a direct consequence of the dysregulated TGF-b signalling in LDS-OECs. The drastic increase of Gremlin-1 was not only confirmed by Western Blotting of LDS-OECs, we also observed significantly elevated Gremlin-1 plasma levels in LDS patients compared to healthy subjects, suggesting that up-regulation of Gremlin-1 was a systemic phenomenon. Although larger studies are needed to confirm increased plasma levels of Gremlin-1 in LDS, our observation may have many practical implications. Determination of Gremlin-1 concentration in peripheral blood may serve as a quick screening assay in patients with vascular abnormalities and direct more EC detailed molecular analysis. Since the median life expectancy in a large study of LDS was only 26 years and many patients with LDS are unrecognized, such a screening assay would permit early disease detection and timely surgical intervention. Furthermore, a future molecularly targeted therapy may be followed by serial determination of Gremlin-1 plasma levels.