Figure 8. Summary model of the effects of Emilin1 deficiency in AV disease.

EMILIN1 is an antagonist of TGFB1.¹⁴ Emilin1 deficiency results in increased TGFB1 signaling through canonical pathways involving phosphorylation of Smad2/3 and non-canonical phosphorylation of Erk1/2. This leads to ECM structural disorganization, disruption of ECM-cell networks, and increased protein interactions of inflammation, fibrosis and immune responses in the adult Emilin1−/− AV before the manifestation of overt AV disease (Early), which is associated with microscale cusp stiffening. In the aged Emilin1−/− AV (Late), ongoing activation of protein networks results in increased proliferation, ECM production and immune recruitment. Increased ECM production leads to overall macroscale tissue-level valve stiffening at the same time that valve dysfunction develops. Observations of early processes improve our understanding of AV disease progression, a necessary step to improve diagnostic and therapeutic tools.