Mechanosensing and mechanoregulation are processes through which the cell responds to stress to maintain a homeostatic state. The fibroblast responds to stress through remodeling of the extracellular matrix (ECM), which includes expression of integrins. Work by Jay D. Humphrey, PhD, Yale University, New Haven, Connecticut, USA, and colleagues is unraveling the role of these processes and their contribution to the development and maintenance of aortic stiffness or large artery stiffness. Arterial stiffness (AS) has been established as an independent predictor of all-cause and cardiovascular (CV) mortality in hypertension [Laurent S et al. Hypertension 2001].

Humphrey reviewed work from their laboratory showing that circumferential AS can be preserved even when structural stiffness increases, largely through wall thickening. Excessive wall thickening reduces stress, but it attenuates reverse remodeling, suggesting ineffective mechanosensing. Despite the focus on intimal medial thickening, adventitial thickening can be dramatic and slow to reverse, particularly when inflammation is present.

AS can cause hypertension. In terms of pathophysiology, Humphrey and colleagues have shown in the setting of intrinsic AS in mouse models that cells work to maintain a constant level of AS, but wall thickness is increased. Ultimately, blood pressure is increased, because there is a responsive increase in pulse wave velocity, earlier return of wave reflections in the cardiac cycle, and augmentation of pressures in the central region.

In terms of mechanobiology, an insidious positive feedback loop has been shown, even in the presence of normal mechanoadaptations. An increase in arterial wall thickness occurs as compensation for an increase in blood pressure, which then increases structural stiffness, in models of induced hypertension. Inflammation appears to complicate this feedback loop, by maintaining the wall thickness. This suggests, says Humphrey, a dysfunctional mechanosensing and mechanoregulation of the ECM.

In a mouse model in which the descending thoracic aorta (DTA) was excised, Humphrey and colleagues showed there is stored energy within tissue that is exposed to stress and strain, i.e., stretch and pressure on the vessels. Thus, they think the primary function of the aorta is to store elastic energy during systole that is used to augment flow during diastole.

Mechanical homeostasis is sought at the subcellular level, in cytoskeletal filaments and fibroblast adhesions; at the cell, cell-cell, and cell-matrix level; and at the tissue and organ level, with altered geometry, structure, and properties and many pathophysiologic responses.

Stretching smooth muscle cells or fibroblasts provides a mechanical stress that can affect many different pathways and ultimately lead to changes in matrix production and degradation and in cell phenotype, Including cell proliferation and contractility. Some of the affected pathways include changes in production of growth factors, stretch-activated channels, an increase in Angiotensin II production (showing it is also autocrine and paracrine in nature), and increased production of monocyte chemoattractant protein-1, which drives inflammation. Changes in contractile protein expression and integrins and their clustering also occurs, showing the cells are able to adapt their ability to sense and regulate the extracellular matrix.

Angiotensin II has been shown to have a role in mechanotransduction pathways and in hypertension. Humphrey and colleagues infused Angiotensin II over a 1-month period into a mouse model and found that systolic, diastolic, and mean blood pressure reached a steady state within 2 weeks. In the DTA, at Day 28, nearly 80% of the wall had adventitial and medial thickening, compared with 20-25% at Day 0. They believe this thickening occurs because the media contains the elastin fibers which store the energy needed to recoil the vessel during systole, diastole, and normal flow. Also, because the adventitia becomes a protective sheath for the more fragile smooth muscle cells and elastin fibrin during the media stress caused by the increased blood pressure. Thus, most of the stress is borne by the adventitia, and this may explain the fibrotic response in adventitia, stated Humphrey. In this model, at about Days 14-21, the cells try to return to homeostasis.

In another mouse model, Humphrey and colleagues found a precipitous loss of stored energy at 3-4 weeks and in circumferential stress, a maladaptive response, and that inflammation caused a “second hit” on top of hypertension that resulted in an added level of fibrosis, another maladaptive response [Bersi MR et al. Hypertension 2016]. In a select subgroup of animals, at 7 months after the Angiotensin II infusion was stopped there was a reduction in blood pressure, but circumferential stress and and wall thickness were not reversed.

Therapeutically, Humphrey suggested a focus on arterial wall thickness, and raised the possibility of integrins as a target. To advance this field, the genetic basis of stiffness and early vascular aging must be better understood, along with elucidating the relations between elastic, muscular, and resistance arteries. Although challenging because of its complexity, the mechanisms of cellular mechanosensing and mechanoregulation of the extracellular matrix must be considered, along with the interactions between mechanobiology and inflammation, particularly within the adventitia and neotintima.

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