Heart valves exhibit a highly-conserved stratified structure exquisitely 
designed to counter biomechanical forces delivered over a lifetime. Heart valve 
structure and competence is maintained by heart valve cells through a process of 
continuous turnover extracellular matrix (ECM). Degenerative (myxomatous) mitral 
valve disease (DMVD) is an important disease associated with aging in both dogs 
and humans. DMVD is increasingly regarded as a disease with identifiable 
signaling mechanisms that control key genes associated with regulation and 
dysregulation of ECM homeostasis. Initiating stimuli for these signaling 
pathways have not been fully elucidated but likely include both mechanical and 
chemical stimuli. Signaling pathways implicated in DMVD include serotonin, 
transforming growth factor β (TGFβ), and heart valve developmental pathways. 
High circulating serotonin (carcinoid syndrome) and serotoninergic drugs are 
known to cause valvulopathy that shares pathologic features with DMVD. Recent 
evidence supports a local serotonin signaling mechanism, possibly triggered by 
high tensile loading on heart valves. Serotonin initiates TGFβ signaling, which 
in turn has been strongly implicated in canine DMVD. Recent evidence suggests 
that degenerative aortic and mitral valve disease may involve pathologic 
processes that mimic osteogenesis and chondrogenesis, respectively. These 
processes may be mediated by developmental pathways shared by heart valves, 
bone, and cartilage. These pathways include bone morphogenic protein (BMP) and 
Wnt signaling. Other signaling pathways implicated in heart valve disease 
include Notch, nitric oxide, and angiotensin II. Ultimately, increased 
understanding of signaling mechanisms could point to therapeutic strategies 
aimed at slowing or halting disease progression.