Abstract Body (Do not enter title and authors here): Background: The primary function of vascular smooth muscle cells (SMCs) is to maintain vascular homeostasis through active contraction and relaxation. Recently we uncovered the SMC-specific long non-coding RNA, Carmn (Cardiac mesoderm enhancer-associated noncoding RNA), as a critical regulator for maintaining visceral SMC contractile phenotype, but its functional role in vascular SMCs remains unknown.
Methods and results: To determine the role of Carmn in vascular SMCs, we generated inducible vascular SMC-specific Carmn KO (ivKO) mice by crossing floxed Carmn mice with the vascular SMC-restricted Itga8-CreER^T2 mouse. We found that Carmn ivKO mice show normal lifespan, but morphological analysis of the mouse thoracic aorta revealed a thinning and dilated vascular wall in ivKO mice compared with control mice. Data from vascular contractility measurements of both carotid and mesenteric arteries showed that vascular contractility in the ivKO mice was impaired compared to control mice. Further, while there was no difference in blood pressure at baseline between ivKO and control mice, as measured by radio telemetry, Angiotensin II-induced elevation of blood pressure was attenuated in ivKO mice. Mechanistically, data from bulk RNA-seq of Carmn-deficient mouse aorta revealed that Carmn deficiency in vascular SMCs leads to downregulation of genes associated with muscle contraction and regulation of blood circulation while increased expression of genes associated with response to inflammation and extracellular matrix remodeling. Consistently, VSMCs in Carmn-deficient aorta displays decreased expression of genes such as Mylk and Dmpk associated with muscle contraction while increased expression of genes associated with tissue remodeling as revealed by single nuclei RNA-seq.
Conclusions: Our data suggest that vascular SMC-restricted deletion of Carmn attenuates vascular contractility and dampens the response to Angiotensin II-induced hypertension through regulating genes involved in muscle contraction. Our study demonstrates that Carmn is critical for maintaining vascular contraction function in mice and suggests Carmn may play an important role in SMC-driven vascular diseases in humans.