Vascular Stiffness Has Two Components, Which Complicates Compensatory Therapeutic Approaches
The present approaches to treating vascular stiffening with age are near entirely compensatory, small molecule drugs that attempt to override signaling and force certain outcomes in the behavior of tissues. This interesting commentary notes that because stiffening has two primary components, compensatory approaches of this nature can produce adverse effects in some circumstances. Stiffening is caused by (a) loss of elasticity in the extracellular matrix of blood vessel walls, and (b) failure of the smooth muscle that controls contraction and dilation to properly respond to environmental cues. Stiffening leads to the raised blood pressure of hypertension, and hypertension causes so much damage to delicate tissues over time that, on its own, it meaningfully raises the risk of age-related disease and mortality in later life.
The mechanical and structural properties of blood vessels differ along the vascular tree. There are two categories of large arteries: elastic and muscular arteries. Elastic arteries are close to the heart, contain more elastin per unit of area and play an important role in buffering the ejected blood volume. More distal muscular arteries have a higher smooth muscle cell content. They regulate wall tension and shear stress by adjusting the vascular tone and transport blood to the smaller resistance vessels that control blood flow.
With increasing age, the structural and cellular components of the arterial wall change. Mechanistically, the arterial wall is largely dependent on the balance between elastin and collagen and their interplay with vascular smooth muscle cell (VSMC) contraction. This balance is disrupted during aging, leading to a higher collagen content, a lower elastin content, more elastin fragmentation, and more cross-linking of both collagen and elastin. On a cellular level, vascular aging is related to endothelial dysfunction and impaired nitric oxide bioavailability, leading to reduced endothelium-dependent vasodilation and therefore more pronounced vasoconstriction. These microstructural and functional changes are typically thought to result in an overall stiffening of the arterial wall.
Researchers have investigated how nitroglycerin (NTG)-mediated vasodilation acutely affects vascular stiffness and whether this differs between elastic and muscular arteries. NTG is an organic nitrate and acts as a nitric oxide (NO) donor. Results show that the arterial stiffness of the carotid artery and the regional carotid-femoral pulse wave velocity (cfPWV) is, as expected, higher in hypertensive individuals than in controls, but this was not observed in the brachial artery. While the stiffness of the elastic carotid artery, as well as cfPWV, increased, the stiffness of the muscular brachial artery did not change significantly. These findings were independent of hypertensive status.
Further analyses revealed that in the carotid artery, the active VSMC stiffness index parameter was lower than the passive ECM stiffness index, whereas these two indices were almost equal in the brachial artery. This leads to the hypothesis that the different stiffness responses to vasodilation are a result of the ratio of active to passive stiffness contributions. When this difference is positive (active stiffness is greater than passive stiffness), decreasing arterial tone will decrease the overall wall stiffness as the active contribution decreases. In contrast, when this difference is negative, vasodilation will lead to an increase in stiffness.
In conclusion, this study highlights the importance of investigating whether vasodilatory drugs, used as antihypertensive medication, have an adverse effect on large arteries by increasing their stiffness, which has inherent potential cardiovascular risks.