The extracellular matrix mechanics in the vasculature

Abstract

Mechanical stimuli from the extracellular matrix (ECM) modulate vascular differentiation, morphogenesis and dysfunction of the vasculature. With innovation in measurements, we can better characterize vascular microenvironment mechanics in health and disease. Recent advances in material sciences and stem cell biology enable us to accurately recapitulate the complex and dynamic ECM mechanical microenvironment for in vitro studies. These biomimetic approaches help us understand the signaling pathways in disease pathologies, identify therapeutic targets, build tissue replacement and activate tissue regeneration. This Review analyzes how ECM mechanics regulate vascular homeostasis and dysfunction. We highlight approaches to examine ECM mechanics at tissue and cellular levels, focusing on how mechanical interactions between cells and the ECM regulate vascular phenotype, especially under certain pathological conditions. Finally, we explore the development of biomaterials to emulate, measure and alter the physical microenvironment of pathological ECM to understand cell-ECM mechanical interactions toward the development of therapeutics.

Fig. 1 |. Mechanotransduction in vascular cells.

Endothelial cells (ECs), pericytes (PCs) and vSMCs rely on a wide array of signaling molecules, transmembrane proteins and cytoskeletal signal transducers to modulate their phenotypes and ECM regulation. Some proteins are expressed in one or two cell types but not the others, and others are expressed in slightly different forms or abundances (such as integrins or vimentin)^,–. CFTR, cystic fibrosis transmembrane receptor; ICAM, intercellular adhesion molecule; IF, intermediate filament; MT, microtubule; NMDAR, N-methyl-d-aspartate receptor; PECAM, platelet and endothelial cell adhesion molecule; SMA, smooth muscle actin; SMMHC, smooth muscle myosin heavy chain; SUN, Sad1p/UNC-84 domain containing; TRPV, transient receptor potential vanilloid.

Fig. 2 |. Overview of the overlapping pathologic changes in vascular cells and their ECM.

During vascular aging and disease, changes in cell behavior and local tissue mechanics result in pathological remodeling of the vascular ECM. Dysregulated ECM turnover and increased proliferation of SMCs are common underlying behaviors in pathologic ECM remodeling in the vasculature^,,,. ECs, endothelial cells; EndMT, endothelial–mesenchymal transition; GAG, glycosaminoglycan; LDL, low-density lipoprotein; oxLDL, oxidized low-density lipoprotein; SASP, senescence-associated secretory phenotype.

Fig. 3 |. Selected approaches to measure cell–ECM mechanical interactions.

a(i–v), AFM measurements of ECM (a(i)), cell indentation (a(ii)), cell (a(iii)), cell in matrix (a(iv)) and tissue (a(v)). a(vi,vii), AFM maps the topography of Epiflex matrix with fibroblasts (a(vi)) and its stiffness (a(vii)). b, Left, TFM approach in which fluorescent beads are seeded in the surrounding ECM as mechanical sensors. b, Right, TFM example: immunofluorescence images of endothelial colony-forming cells (green) with beads (purple) in dynamic hydrogels and non-dynamic hydrogels (top) and quantification of mean and maximum displacement and speed of the beads in time-lapse (bottom) (n = 15 cells from biological triplicates). GFP, green fluorescent protein. c, Left, optical tweezer approach to trap and manipulate a bead in the surrounding ECM. c, Right, a confocal microscopy image of beads seeded in the ECM around an MCF7 cell (top), and the complex modulus │G*│ describes the material’s microscale rigidity depending on frequency, where ω is the frequency and A and b are the fit parameters, with power law behavior at high frequencies (bottom). Low-frequency (LF) and high-frequency (HF) regimes are indicated. d(i–v), Brillouin microscopy (d(i)) with an example of the virtually imaged phased array (VIPA) Brillouin spectrum, ν represents measured Brillouin shift (d(ii)) and average Brillouin shift of cells treated with cytochalasin D (Cyto D; red) with respect to the control (ctrl; blue) (d(iii)), along with examples of Brillouin shift maps (d(iv)) and brightfield images of live U87 cells (control and treated with cytochalasin D) (d(v)).

Fig. 4 |. Modeling vascular ECM in both large vessels and the microvasculature.

Approaches include conduits (TEVGs), hydrogels, microfluidics and synthetic scaffolds^,,. PLGA, polylactic-co-glycolic acid; PEG, polyethylene glycol; bFGF, basic fibroblast growth factor; PVA, polyvinyl acid; GelMA, gel methacrylate; PDMS, polydimethylsiloxane; PGF, placental growth factor.