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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Marie-Luce Bochaton-Piallat,
Q: Dr. Bochaton-Piallat, Dr. Coen, congratulations to your recent publication in the American Journal of Pathology. Can you briefly summarize the rationale and key findings of the study for us?A: During atheromatous plaque formation, SMCs accumulate into the intima and undergo phenotypic changes, i.e. they switch from a quiescent/differentiated phenotype to an activated/dedifferentiated (“atheroma-prone”) phenotype. It has been suggested that a heterogeneous SMC population is already present in the arterial media. The notion of SMC heterogeneity has been reinforced by the description in vitro of morphologically distinct SMC populations in many species (including man). Nevertheless, exporting the concept of SMC heterogeneity from animal models to human has been hampered by the limited availability of human arterial SMCs and difficult experimental standardization.The aim of our study was to reproducibly isolate and thoroughly characterize human arterial SMC subpopulations to evaluate their role in atheroma formation. In this paper we demonstrate that two distinct SMC phenotypes can be isolated from human carotid endarterectomy specimens: large and small SMCs. Small SMCs are selectively isolated from the human carotid artery media only when in the presence of macrophage-derived foam cells from plaques and harbour the features of an atheroma-prone phenotype (i.e. increased proliferative and migratory activities, as well as low level of differentiation). By means of proteomic approach, we identified calmodulin (CaM) as a marker of the small SMC phenotype. Interestingly, using a pharmacologic inhibitor of CaM (W7), we were able to prevent the large-to-small phenotypic switch induced by plaque-derived conditioned medium. Moreover, we also showed that CaM inhibition decreases small SMC proliferative activity. In vivo, CaM is highly expressed by a subpopulation of SMCs in atherosclerotic plaques, thus suggesting a role in atheroma or restenosis developmentQ: Could you please describe the peculiar method you used to obtain the two distinct SMC phenotypes?A: We took advantage of our collaboration with the Unit of Vascular and Endovascular Surgery of Ferrara (Dr. F. Mascoli) who furnished us with endarterectomy specimens. Each specimen was further cut into two portions: a proximal portion, grossly undiseased, and a distal portion (toward the carotid bifurcation) characterized by diffuse atherosclerotic lesions. Media and/or plaque tissues were dissected, cut into small pieces, and placed in the culture dish (explant technique). Media pieces obtained from the undiseased portion gave rise to SMCs exhibiting a large phenotype. Most surprisingly, media pieces from the diseased portion did not produce SMCs when cultured alone; SMCs could be obtained only when media pieces were co-cultured with plaque pieces or plaque derived macrophages, or cultured with plaque-derived conditioned medium. These SMCs were smaller, hence we named them small SMCs, displayed an elongated appearance, grew as multilayers at confluence, and showed increased migratory and proliferative compared to large SMCs.Of particular interest is the fact that, besides reproducibly isolating medial SMC with different characteristics, we discovered that plaque macrophage-derived foam cells are necessary for the selective migration of small SMCs in culture. Moreover, macrophages are capable of inducing a large to small phenotypic transition.Q: Can you speculate about any potential clinical relevance for your discovery? A: Our in vivo demonstration of the capacity of the macrophage-derived foam cells to promote the selective migration of an “atheroma-prone” SMC phenotype, grossly recapitulates what is thought to happen in vivo during the early stages of atherogenesis. We do believe that influencing that modulation of the early interaction between SMCs and macrophage-derived foam cells could possibly slowdown, and ideally prevent atherosclerosis progression, and/or induce plaque regression. Moreover, we believe that CaM, besides becoming a useful marker for the “atheroma-prone” SMC population, could serve as a new target for treatment of atherosclerosis and restenosis.Q: What are the next steps for the future?A: The identification of the macrophage-derived soluble factor(s) capable of inducing the SMC phenotypic selection and modulation is absolutely necessary in the near future. Indeed, we believe it will provide further insight into the development of the early steps of atherosclerotic plaque formation, and will permit us to develop tools for influencing the evolution of atherosclerotic lesions by modulating the crosstalk between SMCs and macrophages. Q: Dr. Bochaton-Piallat, Dr. Coen, thank you for your time to discuss these exciting findings with us.
Am J Pathol. 2013;183:996-1009.