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Antagonism of the 5‐HT2B receptor prevents TGF‐beta1 effects in aortic valve fibroblasts

Transforming growth factor‐β1 (TGF‐β1) causes a phenotypic change in aortic valve interstitial cells (AVICs) that is believed to be a key initiator of degenerative aortic valve disease (DAVD). Activation of certain G protein‐coupled receptors (GPCRs) such as the serotonergic 5‐HT2B receptor (5‐HT2BR) and the angiotensin II type 1 receptor (AT1R) also increases TGF‐β1 activity in AVICs, indicating possible crosstalk between these GPCRs and TGF‐β1 receptors (TβR). Therefore, we hypothesized that the GPCRs, 5‐HT2BR and AT1R, are involved in TGF‐β‐dependent fibrotic responses in AVICs and that antagonists of these receptors can block TGF‐β1 signaling. To test this hypothesis, cultured porcine AVICs were exposed to combinations of 5‐HT2BR and AT1R agonists, antagonists, and TGF‐β1, and their contractile phenotype was quantified by expression of smooth muscle α‐actin (αSMA). Both GPCR agonists led to increased αSMA through Src tyrosine kinase and mitogen‐activated protein kinase pathways, leading to synthesis of TGF‐β1 and subsequent autocrine/paracrine signaling through TβR. Pretreating AVICs with the 5‐HT2BR antagonist SB 204741 prevented increased αSMA expression caused by agonist signaling through both GPCRs and by TGF‐β1. Similarly, the AT1R antagonist ZD7155 inhibited GPCR‐dependent changes, but it did not block TGF‐β1‐mediated changes. These data support the hypothesis that signaling through the 5‐HT2BR enhances both TGF‐β1 protein expression and TGF‐β1 responses. Moreover, antagonism of the 5‐HT2BR prevents TGF‐β1‐mediated phenotypic change in AVICs, indicating that this GPCR may be a viable target to treat DAVD. In contrast, the AT1R regulates autocrine production of TGF‐β1, but not downstream regulation of αSMA.