Abstract MP02: Proprotein Convertase Subtilisin/kexin Type 6 (PCSK6) Is Involved In Regulation Of Vasculogenesis

Background: PCSK6 cleaves and activates growth factors involved in cell differentiation and Pcsk6-/- mice exhibit 25% embryonic lethality, while surviving offspring have blindness and cyclopia. We have shown that PCSK6 localizes to vascular smooth muscle cells of intra-plaque neovessels. Hypothesis: We hypothesize that a) the processes of vasculogenesis, atherosclerosis and plaque neovascularisation share common molecular regulators and b) that PCSK6 plays a common role in vascular remodeling. Methods: Association between SNPs near the PCSK6 gene and levels of 90 plasma proteins was tested using data from 30,931 individuals in the SCALLOP consortium. Data from the FinnGen consortium (Release 3) were queried to explore the PCSK6 SNPs associated with specific disease phenotypes. Morpholino technology was used for Pcsk6 knockdown in zebrafish, coupled with vascular phenotype studies. Pcsk6-/- mice were used to study the expression of vasculogenesis related genes as well as vascular morphology. Results: Rs7178801 and rs11639051 in the PCSK6 gene were found to relate to plasma PDGFB and VEGFD levels, while rs45482895 associated with diabetic retinopathy and disorders of the choroid and retina in humans. Gross phenotypic and histological examination of zebrafish embryos with ablated PCSK6 showed improper peripheral vascular patterning of intersegmental vessels, cerebral and myocardial haemorrhage, atrial dilatation and pericardial oedema. Gene expression levels of vasculogenesis related genes, i.e. Vegfa, Vegfb, Angpt1 and Tgfb2 were altered in the heart, liver and adipose tissue in Pcsk6-/- mice. In the retinas of Pcsk6-/- mice, Pdgfb was significantly downregulated compared to controls. Staining of the retinal vasculature showed that superficial retinal vasculature had a lower number of branching points and vessel width, while deep retinal vasculature covered a significantly smaller area in Pcsk6-/- Conclusions: Here, we show that variants in the PCSK6 gene associate with growth factors implicated in vasculogenesis and retinopathy. Lack of Pcsk6 in mice and zebrafish led to vascular patterning defects. Further studies will aim to elucidate the mechanisms by which PCSK6 regulates vasculogenesis in homeostatic and pathological conditions