Aortic Valve Cyclic Stretch Causes Increased Remodeling Activity and Enhanced Serotonin Receptor Responsiveness

Abstract

Background Increased serotonin(5HT) receptor(5HTR) signaling has been associated with cardiac valvulopathy. Prior cell culture studies of 5HTR signaling in heart valve interstitial cells have provided mechanistic insights concerning only static conditions. We investigated the hypothesis that aortic valve biomechanics participate in the regulation of both 5HTR expression and inter-related extracellular matrix remodeling events. Methods The effects of cyclic-stretch on aortic valve 5HTR, expression, signaling and extracellular matrix remodeling were investigated using a tensile stretch bioreactor in studies which also compared the effects of adding 5HT and/or the 5HT-transporter inhibitor, Fluoxetine. Results Cyclic-stretch alone increased both proliferation and collagen in porcine aortic valve cusp samples. However, with cyclic-stretch, unlike static conditions, 5HT plus Fluoxetine caused the greatest increase in proliferation (p<0.0001), and also caused significant increases in collagen(p<0.0001) and glycosaminoglycans (p<0.0001). DNA microarray data demonstrated upregulation of 5HTR2A and 5HTR2B (>4.5 fold) for cyclic-stretch versus static (p<0.001), while expression of the 5HT transporter was not changed significantly. Extracellular matrix genes (eg. Collagen Types I,II,III, and proteoglycans) were also upregulated by cyclic-stretch. Conclusions Porcine aortic valve cusp samples subjected to cyclic stretch upregulate 5HTR2A and 2B, and also initiate remodeling activity characterized by increased proliferation and collagen production. Importantly, enhanced 5HTR responsiveness, due to increased 5HTR2A and 2B expression, results in a significantly greater response in remodeling endpoints (proliferation, collagen and GAG production) to 5HT in the presence of 5HT transporter blockade.

Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve

“…The cyclic mechanical loading of the valves during the cardiac cycle has been shown to trig- ger a number of cellular processes within the cardiovascular system (17,35). We asked if cyclic strain potentiated EMT in our engineered valve endothelium via increased expression of the mesenchymal marker α-smooth muscle actin (α-SMA) and downregulation of endothelial markers VE-cadherin and CD31 (36).…”

Valve interstitial cell tensional homeostasis directs calcification and extracellular matrix remodeling processes via RhoA signaling

“…These changes influence VIC phenotype and modulate VIC interactions with their environs [9, 10]. Strain state regulates VIC cytokine secretion [11,12], calcification [13], collagen synthesis [14], alignment [15], and proliferation [16]. Extracellular matrix composition influences VIC homeostasis [17], in part through modulation of leaflet [18] and cellular [19] stiffness.…”

Hemodynamic and Cellular Response Feedback in Calcific Aortic Valve Disease

“…Multiple ex vivo and in vitro studies have demonstrated that pathological stretch of valve tissue or isolated VICs can elicit responses associated with valve disease development, most notably increased matrix synthesis and remodeling 45,[105][106][107] and VIC activation to the secretory myofibroblast phenotype. 44,45,106,108 These findings have potentially provocative implications linking pathological stretch with the deterioration in aortic valve tissue properties and function that occurs with disease.…”