Titin is a new factor regulating arterial stiffness through vascular smooth muscle cell tone in male rats

Arterial stiffness is a robust predictor of cardiovascular disease and mortality. As such, there is substantial interest in uncovering its causal factors for the development of targeted treatments to regulate arterial stiffness. The elastic protein titin is a key determinant of myocardial stiffness, yet whether it plays a role in regulating arterial stiffness is unknown. In this study, we aimed to investigate the role of titin in vascular smooth muscle cell (VSMC) and overall arterial stiffness. To do this, we took advantage of rats lacking RNA binding motif 20 (RBM20), the primary splicing regulator of titin, in striated muscles. Using this model, we demonstrate that RBM20 regulates titin isoform expression in smooth muscle, with loss of the protein leading to the expression of larger titin isoforms. We show that the expression of larger titin reduces the stiffness of VSMCs. While decreased titin-based VSMC stiffness did not affect baseline arterial stiffness, we found that arterial stiffness was reduced in response to a challenge with the potent vasoconstrictor angiotensin II (Ang II). The observed reduction in arterial stiffness following Ang II treatment was not the result of changes in either the extracellular matrix or myofilaments. We further show that the expression of a larger titin isoform ameliorates cardiac remodeling caused by Ang II-associated hypertension. In summary, our study provides the first evidence that titin regulates VSMC stiffness, which is relevant for arterial stiffness in the context of elevated blood pressure. Furthermore, our data provide proof-of-concept evidence that targeting RBM20 to reduce arterial stiffness through titin isoform switching may benefit aging- or hypertension-associated arterial stiffness and vascular diseases.