Mechanobiology and the Microcirculation: Cellular, Nuclear and Fluid Mechanics

Abstract

Endothelial cells are stimulated by shear stress throughout the vasculature and respond with changes in gene expression and by morphological reorganization. Mechanical sensors of the cell are varied and include cell surface sensors that activate intracellular chemical signaling pathways. Here, possible mechanical sensors of the cell including reorganization of the cytoskeleton and the nucleus are discussed in relation to shear flow. A mutation in the nuclear structural protein lamin A, related to Hutchinson Gilford progeria syndrome, is reviewed specifically since the mutation results in altered nuclear structure and stiffer nuclei; animal models also suggest significantly altered vascular structure. Nuclear and cellular deformation of endothelial cells in response to shear stress provides partial understanding of possible mechanical regulation in the microcirculation. Increasing sophistication of fluid flow simulations inside the vessel is also an emerging area relevant to the microcirculation since visualization in situ is difficult. This integrated approach to study -including medicine, molecular and cell biology, biophysics and engineering -provides a unique understanding of multi-scale interactions in the microcirculation.

Mechanics of the Nucleus

“…It was proposed that alignment of vascular endothelial cells in the direction of flow, as consistently seen in vitro and in vivo , could be explained by cells trying to minimize the force acting on the nucleus (76). Consequently, alterations in nuclear structure and stiffness due to mutations or disease could have significant affects on endothelial mechanotransduction and cell function (38). …”

“…Even though vascular smooth muscle cells are most affected in the cardiovascular phenotype of HGPS, recent evidence suggest that the phenotype could also be, at least in part, mediated by endothelial cells, as endothelial cells expressing progerin have an impaired response to fluid shear stress (38, 154). The importance of (normal) nuclear mechanics to the physiological response to shear stress is further supported by the recent finding that nuclei of endothelial cells subjected to fluid shear stress show persistent changes in nuclear shape and stiffness, acting as a stress-bearing organelle (37, 46).…”

Lamins at a glance

“…In contrast to lamin-deficient cells, cells from patients with HutchinsonGilford progeria syndrome (HGPS) develop increasingly stiffer nuclei (Dahl et al, 2006;Verstraeten et al, 2008), possibly as a result of accumulation of progerin at the nuclear envelope. Interestingly, HGPS cells and cells lacking A-type lamins are more susceptible to mechanically induced cell death (Lammerding et al, 2004;Verstraeten et al, 2008), providing a possible mechanism for the progressive loss of vascular smooth muscle cells in blood vessels and the arteriosclerotic disease in HGPS (Capell et al, 2007;Dahl et al, 2010;Gerhard-Herman et al, 2012Merideth et al, 2008Stehbens et al, 2001) and muscle loss in EDMD. In addition to affecting nuclear stability, loss of A-type lamins and mutations linked to EDMD can also disrupt nucleo-cytoskeletal coupling, resulting in the loss of synaptic nuclei from neuromuscular junctions (Méjat et al, 2009), impaired nuclear movement and positioning and disturbed cytoskeletal organization (reviewed by Méjat and Misteli, 2010).…”

Microscale flow propulsion through bioinspired and magnetically actuated artificial cilia

“…21 Recent studies also indicated that in the inner lining of a blood vessel wall, endothelial cells play an important role in regulating downstream intracellular responses and modulating the gene/protein expression pathway through the conversion of the wall shear stress load to biochemical signals. [22][23][24][25] Specifically, one of the major findings from the perspective of fluid dynamics concluded that the human aortic endothelial cells are more inclined to proliferate in an oscillatory flow rather than an unidirectional laminar one. 22 Therefore, a microfluidic device, which can periodically generate a time-dependent/reversible flow in addition to a uniform flow, is practically advantageous for RBC-related assessments performed on a portable chip.…”