Aortic valve stenosis (AVS) is the progressive calcification and loss-of-function of the aortic valve, leading to heart failure, left-ventricular hypertrophy and ultimately death. Despite affecting 3% of the population over 65 years there exists no drug treatment for AVS, leaving invasive surgery as the only option. Critical to the progression of AVS is the neovascularisation of the aortic valve leaflets. This allows for the infiltration of immune cells, such as macrophage and monocytes, into the valve tissue resulting in an inflammatory and proliferative response. The resultant tissue hypoxia stimulates angiogenesis and AVS disease progression. Inhibiting angiogenesis is therefore an attractive potential target for the treatment of AVS. The aim of this study was to determine the role of angiogenesis mediators during aortic valve neovascularisation and the progression of AVS Human aortic valve tissue was obtained by informed consent from patients undergoing aortic valve replacement surgery at Aberdeen Royal Infirmary. In vitro techniques were performed using isolated and cultured primary human aortic valve interstitial cells (VICs). Immunohistochemistry of CD31 positive endothelial cells within human aortic valves showed that diseased aortic valves had significantly increased intravalvular vessel number in comparison to healthy aortic valves (results expressed as mean ± SEM; control – 3.93 ± 1.25 vessels/mm2 versus diseased – 14.93 ± 2.69 vessels/mm2, p < 0.01, n=10). Soluble fms-like tyrosine kinase 1 (sFlt1) is a soluble isoform of the VEGF Receptor 1 which acts to inhibit angiogenesis by sequestering VEGF and thereby preventing signalling via the membrane-bound VEGF receptors. Hypoxia (induced by incubation in a hypoxic chamber at 1% O2, 5% CO2), which is observed within valve tissue after the onset of AVS progression, reduced the protein expression of sFlt1 (results expressed mean ± SEM; 0.54 ± 0.11 fold decrease in sFlt1 protein expression vs normoxic control after 24hr hypoxia incubation, p=<0.05, n=6) siRNA knockdown of sFlt1 on cultured VICs indicate that loss of sFlt1 promotes angiogenesis in vitro using a HUVEC based assay measuring endothelial tubule formation (results expressed mean ± SEM; 31.3% ± 13.6% increase in tubule formation in sFlt1 siRNA knockdown compared to control siRNA, p<0.05, n=6). Together this demonstrates that hypoxia-induced modulation of pro- and anti-angiogenic factors is able to promote angiogenesis in aortic valves. In summary, this data suggests that sFlt1 is an important factor in maintaining aortic valve avascularity. We have also shown that sFlt-1 reduction is caused by the pathologically relevant hypoxic changes which occur during the progression of AVS. Together this work highlights the potential of sFlt1 as a therapeutic target in the treatment of AVS via the prevention of intravalvular neovascularisation.