Smooth Muscle Cells: To Be or Not To Be? Response to Nguyen et al

The conversion of contractile vascular smooth muscle cells (SMCs) to a synthetic or proliferative phenotype is thought to play a major role in vascular diseases, such as atherosclerosis and restenosis.1–3 Our recent work presents evidence that challenges this widely accepted dogma. Our findings suggest that multipotent vascular stem cells (MVSCs) are a major contributor to vascular remodeling.4 The experimental results demonstrate that the major population of the traditionally defined proliferative/synthetic SMCs is derived from the differentiation of MVSCs rather than the dedifferentiation of mature SMCs. Both in vitro and in vivo results suggest that vascular disease is a stem cell disease, which raises the question on the previous dogma: Is vascular disease a SMC disease? In this issue of Circulation Research , a group of leaders in the area of SMC biology wrote a commentary on this work.5 They present evidence in the literature that seems to support the SMC dedifferentiation hypothesis. However, in many previous studies, it was incorrectly assumed that the vascular cells in the primary culture and in injured blood vessels were mostly derived from SMCs. Thus, the previous experimental findings on vascular cells were often attributed to SMCs, which resulted in data misinterpretation and the overstatement on SMC functions. We agree that further investigations are needed to determine the relative contribution of MVSCs and SMCs to vascular remodeling in various animal models; however, we respectfully disagree on some of the arguments in the commentary. Vascular SMC biology has been studied in vitro and in vivo extensively in the past 50 years since the method for SMC culture was established. The concept of phenotypic modulation of SMCs was originated from the ultrastructural characterization of SMC culture in 1960s to 1970s, which has been summarized in the comprehensive review by Chamley-Campbell et al. …