A Demonstration that Smooth Muscle Cell Dysfunction Contributes Significantly to Age-Related Vascular Stiffening
A few different mechanisms plausibly contribute to the stiffening of blood vessels that takes place with aging. This is one of the most harmful aspects of aging, as it causes hypertension by upsetting the feedback mechanisms that control blood pressure. Hypertension in turn damages organ tissues, weakens the heart, and raises the risk of fatal rupture of a weakened blood vessel. The mechanisms of interest include (a) calcification, which may be secondary to inflammation and cellular senescence, (b) the formation of persistent cross-links in the extracellular matrix, degrading structural properties such as elasticity, and (c) dysfunction in the smooth muscle responsible for contraction and dilation of blood vessels.
We can hope that calcification will be improved by senolytic therapies to clear senescent cells, and that near future cross-link breakers based on programs funded by the SENS Research Foundation will make short work of that contribution of cross-links to degenerative aging. Dysfunctional smooth muscle cells are more of a problem, however, as it is far from clear as to what exactly is going wrong and how it might be effectively addressed. In this paper, the researchers mount what I think is a fairly convincing demonstration that this cellular dysfunction is significant and distinct from other factors related to vascular stiffening, and is inherent to the cells rather than being caused directly by the environment of the surrounding aged tissue. This calls for more attention to be directed towards this part of the problem.
Increased aortic stiffness, whatever the underlying cause, is also an independent predictor of outcomes of cardiovascular diseases in the elderly. It is well known that hypertension is a highly age-related human disease. Despite a widely held belief that increased aortic stiffness in hypertensive patients is largely a manifestation of long-standing hypertension-related damage, a recent statement from the American Heart Association (AHA) asserts that aortic stiffening is a cause rather than a consequence of hypertension in middle-aged and older individuals.
Our recent studies with atomic force microscopy (AFM) have demonstrated similar characteristics of aortic vascular smooth muscle cells (VSMCs) in both aging and hypertension, indicating that VSMC-mediated regulation is a fundamental basis of aortic stiffening in both conditions. However, the underlying mechanisms are not fully understood. It is conceivable that, in addition to intracellular effects, VSMCs are able to contribute to aortic stiffening via extracellular effects. However, it is difficult to discern the extracellular effects of VSMCs in intact aortic tissue in vivo.
In our previous study, integrin β1 was found to be significantly increased in VSMCs from stiffened aortas in aging monkeys, indicating that integrin β1 may contribute to aortic stiffening. Other recent studies emphasize the potential role of Lysyl oxidase (LOX) in vascular remodeling and the regulation of the biomechanical properties of the extracellular matrix (ECM). Different patterns of LOX expression/activity have been associated with distinct vascular pathological processes. For example, downregulation of LOX has been associated with destructive remodeling of arteries during aorta aneurysm (AA) development. Deletion of the mouse LOX gene promotes fragmentation of elastic fibers and VSMC discontinuity in the aortic wall. Loss-of-function mutations of LOX can cause AAs and aortic stiffening in humans. These studies indicate an essential role of LOX in maintaining the tensile and elastic features of blood vessels.
The present study tests our hypothesis that aortic VSMCs contribute to aortic wall stiffness via both increased intrinsic stiffness and extracellular dysregulation mediated through altered regulation of integrin and LOX signaling. Firstly, aortic stiffening was confirmed in spontaneously hypertensive rats (SHRs) versus Wistar-Kyoto (WKY) rats. Vascular smooth muscle cells were isolated from thoracic aorta and embedded into an in vitro 3D model to form reconstituted vessels. Reconstituted vessel segments made with SHR VSMCs were significantly stiffer than vessels made with WKY VSMCs. SHR VSMCs in the reconstituted vessels exhibited different morphologies and diminished adaptability to stretch compared to WKY VSMCs, implying dual effects on both static and dynamic stiffness. Mechanistically, compared to WKY VSMCs, SHR VSMCs exhibited an increase in the levels of active integrin β1- and bone morphogenetic protein 1 (BMP1)-mediated proteolytic cleavage of lysyl oxidase (LOX).