Vascular pathobiology of pulmonary hypertension
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Keywords:
Crosstalk
Mural cell
Cell type
Pathogenesis
Platelet-derived growth factor
An externally regulated delivery model that permits temporal separation of multiple angiogenic factors was used for the delivery of basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). While bFGF plays a significant role in the sprouting of new capillaries, PDGF plays a role in the recruitment of mural cells, which stabilize neovessels. However, these two factors have been shown to inhibit each other, when presented together. Using the externally regulated model, sequential delivery of bFGF and PDGF led to not only increased endothelial cell migration, but also endothelial cell and vascular pericyte colocalization. More importantly, this delivery strategy was able to induce red blood cell-filled neovessels, suggesting integration of angiogenesis with the existing vasculature.
Mural cell
Platelet-derived growth factor
Pericyte
Colocalization
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Rationale: Vascular smooth muscle cell (VSMC) accumulation is a hallmark of atherosclerosis and vascular injury. However, fundamental aspects of proliferation and the phenotypic changes within individual VSMCs, which underlie vascular disease, remain unresolved. In particular, it is not known whether all VSMCs proliferate and display plasticity or whether individual cells can switch to multiple phenotypes. Objective: To assess whether proliferation and plasticity in disease is a general characteristic of VSMCs or a feature of a subset of cells. Methods and Results: Using multicolor lineage labeling, we demonstrate that VSMCs in injury-induced neointimal lesions and in atherosclerotic plaques are oligoclonal, derived from few expanding cells. Lineage tracing also revealed that the progeny of individual VSMCs contributes to both alpha smooth muscle actin (aSma)–positive fibrous cap and Mac3-expressing macrophage-like plaque core cells. Costaining for phenotypic markers further identified a double-positive aSma+ Mac3+ cell population, which is specific to VSMC-derived plaque cells. In contrast, VSMC-derived cells generating the neointima after vascular injury generally retained the expression of VSMC markers and the upregulation of Mac3 was less pronounced. Monochromatic regions in atherosclerotic plaques and injury-induced neointima did not contain VSMC-derived cells expressing a different fluorescent reporter protein, suggesting that proliferation-independent VSMC migration does not make a major contribution to VSMC accumulation in vascular disease. Conclusions: We demonstrate that extensive proliferation of a low proportion of highly plastic VSMCs results in the observed VSMC accumulation after injury and in atherosclerotic plaques. Therapeutic targeting of these hyperproliferating VSMCs might effectively reduce vascular disease without affecting vascular integrity.
Neointima
Lineage markers
Mural cell
Pericyte
Neointimal hyperplasia
Phenotypic switching
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Abstract Vascular smooth muscle cells (VSMCs) are the most abundant cell in vessels. Earlier experiments have found that VSMCs possess high plasticity. Vascular injury stimulates VSMCs to switch into a dedifferentiated type, also known as synthetic VSMCs, with a high migration and proliferation capacity for repairing vascular injury. In recent years, largely owing to rapid technological advances in single-cell sequencing and cell-lineage tracing techniques, multiple VSMCs phenotypes have been uncovered in vascular aging, atherosclerosis (AS), aortic aneurysm (AA), etc. These VSMCs all down-regulate contractile proteins such as α-SMA and calponin1, and obtain specific markers and similar cellular functions of osteoblast, fibroblast, macrophage, and mesenchymal cells. This highly plastic phenotype transformation is regulated by a complex network consisting of circulating plasma substances, transcription factors, growth factors, inflammatory factors, non-coding RNAs, integrin family, and Notch pathway. This review focuses on phenotypic characteristics, molecular profile and the functional role of VSMCs phenotype landscape; the molecular mechanism regulating VSMCs phenotype switching; and the contribution of VSMCs phenotype switching to vascular aging, AS, and AA.
Phenotypic switching
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Interactions between vascular endothelial cells and the underlying smooth muscle cells (VSMCs) are of paramount importance in maintaining vascular functions. Calmodulin (CaM) is involved in a wide variety of cellular functions and is a limiting factor in both cell types, with free cytoplasmic CaM constituting only a small fraction of the total cellular CaM. Currently nothing is known about potential interactions between ECs and VSMCs as it involves CaM. We have begun to investigate the possibility that vascular endothelial cells impact VSMC functions via CaM‐dependent activities. Using a co‐culture model of primary culture vascular endothelial cells and smooth muscle cells isolated from the same vessels, we have found that VSMCs in co‐culture with proliferating ECs express on average 90% more CaM than monocultured VSMCs. Media fractionation and eNOS inhibition experiments indicate that the CaM‐elevating effect was exerted by a soluble factor that is not nitric oxide. The CaM‐elevating effect exerted by ECs is strongly dependent on endothelial density, such that at a starting 50% confluency of VSMCs, a starting 20% endothelial confluency triggers the greatest CaM increase in VSMCs, whereas a starting 70% endothelial confluency yields no visible effect on VSMC CaM expression after 48 hrs. Pharmacological inhibition of cyclooxygenase‐1, vascular endothelial cell growth factor (VEGF), and endothelin‐1 receptors (ET A and ET B ) does not affect the observed increase in CaM. The data suggest that proliferating endothelial cells produce a soluble factor that can regulate CaM‐dependent signaling in VSMCs via alterations in total cellular CaM expression.
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Background— Tumor blood vessels are both structurally and functionally abnormal compared with normal vessels. A limited support of mural cells may contribute to these abnormalities. Here, we characterized mural cell recruitment in 2 mouse tumor models and addressed the question of why tumor vessels fail to recruit a proper coat of mural cells. Methods and Results— We studied mural cell recruitment to the vasculature of 2 transplantable mouse tumor models, T241 fibrosarcoma and KRIB osteosarcoma. We found that both tumors formed a vessel network with heterogeneous and highly abnormal organization of mural cells. Transplantation of tumors to mice expressing lacZ in mural cells demonstrated that these cells were host-derived. Although tumor vessel endothelium expressed PDGF-B, an embryonic mitogen for mural cells, only very few PDGFRβ-positive cells were found to be associated with the developing tumor vasculature, suggesting a limited pool of recruitable mural cells. We tested whether exogenous mural cells ...
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Loss of contractility and acquisition of an epithelial phenotype of vascular smooth muscle cells (VSMCs) are key events in proliferative vascular pathologies such as atherosclerosis and post-angioplastic restenosis. There is no proper cell culture system allowing differentiation of VSMCs so that it is difficult to delineate the molecular mechanism responsible for proliferative vasculopathy. We investigated whether a micropatterned substrate could restore the contractile phenotype of VSMCs in vitro. To induce and maintain the differentiated VSMC phenotype in vitro, we introduced a micropatterned groove substrate to modulate the morphology and function of VSMCs. Later than 7th passage of VSMCs showed typical synthetic phenotype characterized by epithelial morphology, increased proliferation rates and corresponding gene expression profiles; while short-term culture of these cells on a micropatterned groove induced a change to an intermediate phenotype characterized by low proliferation rates, increased migration, a spindle-like morphology associated with cytoskeletal rearrangement and expression of muscle-specific genes. Microarray analysis showed preferential expression of contractile and smooth muscle cell-specific genes in cells cultured on the micropatterned groove. Culture on a patterned groove may provide a valuable model for the study the role of VSMCs in normal vascular physiology and a variety of proliferative vascular diseases.
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Primary (astronomy)
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The historical view of vascular smooth muscle cells (VSMCs) in atherosclerosis is that aberrant proliferation of VSMCs promotes plaque formation, but that VSMCs in advanced plaques are entirely beneficial, for example preventing rupture of the fibrous cap. However, this view has been based on ideas that there is a homogenous population of VSMCs within the plaque, that can be identified separate from other plaque cells (particularly macrophages) using standard VSMC and macrophage immunohistochemical markers. More recent genetic lineage tracing studies have shown that VSMC phenotypic switching results in less-differentiated forms that lack VSMC markers including macrophage-like cells, and this switching directly promotes atherosclerosis. In addition, VSMC proliferation may be beneficial throughout atherogenesis, and not just in advanced lesions, whereas VSMC apoptosis, cell senescence, and VSMC-derived macrophage-like cells may promote inflammation. We review the effect of embryological origin on VSMC behavior in atherosclerosis, the role, regulation and consequences of phenotypic switching, the evidence for different origins of VSMCs, and the role of individual processes that VSMCs undergo in atherosclerosis in regard to plaque formation and the structure of advanced lesions. We think there is now compelling evidence that a full understanding of VSMC behavior in atherosclerosis is critical to identify therapeutic targets to both prevent and treat atherosclerosis.
Phenotypic switching
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Fibrous cap
Foam cell
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The platelet-derived growth factor (PDGF) signaling pathway is essential for inducing a dedifferentiated state of vascular smooth muscle cells (VSMCs). Activation of PDGF inhibits smooth muscle cell (SMC)-specific gene expression and increases the rate of proliferation and migration, leading to dedifferentiation of VSMCs. Recently, microRNAs have been shown to play a critical role in the modulation of the VSMC phenotype in response to extracellular signals. However, little is known about microRNAs regulated by PDGF in VSMCs. Herein, we identify microRNA- 15b (miR-15b) as a mediator of VSMC phenotype regulation upon PDGF signaling. We demonstrate that miR-15b is induced by PDGF in pulmonary artery smooth muscle cells and is critical for PDGF-mediated repression of SMC-specific genes. In addition, we show that miR-15b promotes cell proliferation. These results indicate that PDGF signaling regulates SMC-specific gene expression and cell proliferation by modulating the expression of miR-15b to induce a dedifferentiated state in the VSMCs.
Platelet-derived growth factor
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Pericyte
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Osteonectin
matrix Gla protein
Mural cell
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