Abstract
ObjectivesVascular disorders are associated with phenotypical switching of vascular smooth muscle cells (VSMCs). We investigated the effect of bone morphogenetic protein (BMP)‐2 in controlling VSMC phenotype and vascular disorder progression. Lysine (K)‐specific demethylase 1A (KDM1A) has been identified to target BMP‐2 and is employed as a therapeutic means of regulating BMP‐2 expression in VSMCs.Materials and methodsVSMCs were stimulated with angiotensin II, and the expression of KDM1A and BMP‐2 was detected. VSMC proliferation, apoptosis, and phenotype were evaluated. An in vivo aortic injury model was established, and VSMC behaviour was evaluated by the expression of key markers. The activation of BMP‐2–associated signalling pathways was examined.ResultsWe confirmed the inhibitory effect of KDM1A on BMP‐2 activity and demonstrated that KDM1A inhibition prevented VSMC transformation from a contractile to synthetic phenotype. In angiotensin II‐treated VSMCs, KDM1A inhibition triggered a decrease in cell proliferation and inflammatory response. In vivo, KDM1A inhibition alleviated post‐surgery neointimal formation and collagen deposition, preventing VSMCs from switching into a synthetic phenotype and suppressing disease onset. These processes were mediated by BMP‐2 through canonical small mothers against decapentaplegic signalling, which was associated with the activation of BMP receptors 1A and 1B.ConclusionsThe regulatory correlation between KDM1A and BMP‐2 offers insights into vascular remodelling and VSMC phenotypic modulation. The reported findings contribute to the development of innovative strategies against vascular disorders.
Highlights
Neointimal hyperplasia is a pathological process that often occurs after surgical intervention in vascular diseases such as pulmonary arterial hypertension and is the main contributor to post‐interven‐ tion restenosis.[1]
Knowing that downstream bone morphogenetic protein (BMP)/BMP‐2 receptors (BMPRs) signalling is critically im‐ plied in small mothers against decapentaplegic (SMAD) activity, we investigated the behaviour of BMP‐2 itself and receptors 1A, 1B, and 2 after aortic endothelial balloon injury was carried out in rats
The findings of our in vitro study collectively showed that the inhibition of KDM1A expression significantly downplayed the effect of angiotensin II (Ang‐II) in the induction of contractile‐to‐ synthetic phenotypic modulation in vascular smooth muscle cells (VSMCs) (Figure 3A,B)
Summary
Neointimal hyperplasia is a pathological process that often occurs after surgical intervention in vascular diseases such as pulmonary arterial hypertension and is the main contributor to post‐interven‐ tion restenosis.[1]. The phenotypic transformation of VSMCs is mainly induced by growth factors (eg, angiotensin II), mechanical stimulation, and molecular signalling. The stimulation signal is transmitted to the nucleus and eventually regulates the expression of smooth muscle cell differentiation marker genes.[8,9,10] Among the members of the bone morphogenetic protein (BMP) multifunctional cytokine family, BMP‐2 is a well‐known osteogenic factor[11,12] that plays critical roles in embryonic development,[13,14] nerve growth,[15,16] and cell be‐ haviour regulation.[17] BMP‐2 signalling can occur via either canonical or non‐canonical routes. Non‐canonical BMP signalling triggers non‐SMAD activity including mitogen‐activated protein kinase and phosphoinositide 3 kinase pathways.[18,19] In tumour‐related studies, BMP‐2 has demonstrated an inhibitory effect on colon cancer cell growth and proliferation while promoting apoptosis.[20,21] In addition, BMP‐2 signalling is involved in the maintenance of the contractile phenotype and has been shown to inhibit VSMC proliferation and neointimal hyperplasia.[22,23] Whether BMP‐2 signalling is mediated by canonical or non‐canonical routes in vascular remodelling re‐ mains to be investigated
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