title: Cell-shape regulation of smooth muscle cell proliferation.
abstract: Vascular smooth muscle cells (SMCs) play an important role in vascular remodeling. Heterogeneity and phenotypic changes in SMCs are usually accompanied by a morphological difference, i.e., elongated/spindle-like versus spread-out or epithelioid/rhomboid cell shapes. However, it is not known whether the cell shape directly regulates SMC proliferation, and what the underlying mechanisms are. In this study, microgrooves and micropatterned matrix islands were used to engineer the cell shape and investigate the associated biophysical and biological mechanisms. Compared to spread-out SMCs on nonpatterned surfaces, SMCs on micropatterned surfaces demonstrated elongated morphology, significantly lower cell and nucleus shape indexes, less spreading, a lower proliferation rate, and a similar response (but to a lesser extent) to platelet-derived growth factor, transforming growth factor-beta, and mechanical stretching. DNA microarray profiling revealed a lower expression of neuron-derived orphan receptor-1 (NOR-1) in elongated SMCs. Knocking down NOR-1 suppressed DNA synthesis in SMCs, suggesting that NOR-1 is a mediator of cell elongation effects. Regulation of DNA synthesis in SMCs by the cell shape alone and a decrease in DNA synthesis in the case of small cell spreading area were achieved by micropatterning SMCs on matrix islands of different shapes and spreading areas. Changes in the cell shape also affected the nucleus shape, whereas variations in the cell spreading area modulated the nucleus volume, indicating a possible link between nucleus morphology (both shape and volume) and DNA synthesis. The findings of this investigation provide insight into cell shape effects on cell structure and proliferation, and have direct implications for vascular pathophysiology.
authors.affiliation: Department of Bioengineering, University of California, Berkeley, California, USA.
authors.forename: Rahul G
authors.initials: RG
authors.lastname: Thakar
authors.forename: Qian
authors.initials: Q
authors.lastname: Cheng
authors.forename: Shyam
authors.initials: S
authors.lastname: Patel
authors.forename: Julia
authors.initials: J
authors.lastname: Chu
authors.forename: Mansoor
authors.initials: M
authors.lastname: Nasir
authors.forename: Dorian
authors.initials: D
authors.lastname: Liepmann
authors.forename: Kyriakos
authors.initials: K
authors.lastname: Komvopoulos
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D053144:Cell Nucleus Shape; D049109:Cell Proliferation; D048430:Cell Shape; D004247:DNA / Q000096:biosynthesis; D016172:DNA Fingerprinting; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004129:Dimethylpolysiloxanes; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008567:Membranes, Artificial; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D054457:Tissue Scaffolds
chemical_list: D004268:DNA-Binding Proteins; D004129:Dimethylpolysiloxanes; D036341:Intercellular Signaling Peptides and Proteins; D008567:Membranes, Artificial; C490412:NR4A3 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C013830:baysilon; D004247:DNA