**5. Effect of diseased states**

Each component implicated in the regulation of tone has a multitude of signals being produce that is intended to affect a vasomotor response from the VSMCs. Signals from myogenic, shear, metabolic, and neurovascular influences may be additive or opposing in their effect on VSMCs and further combine with one another creating intricate and precise regulation of cerebral vascular tone. It is this intricacy however, that also introduces many possible steps in the pathway for an abnormal response to occur. As such changes to the regulation of tone may form the basis of several pathologies including MetS. The contributing risk factors associated with MetS alter the local regulation of cerebral vascular tone by inducing changes in both the structure and function of the vessels. These risk factors include hypertension, T2DM, and obesity

which promote a pro-inflammatory pro-oxidant state. Functionally, MetS is highly linked to increased smooth muscle activation and endothelial dysfunction which has important implications for the ability of a vessel to dilate in response to a multitude of stimuli previously discussed including hypotension, shear, hypoxia, and other metabolic stimuli. Increased myogenic properties are consistently overserved in MetS in multiple vascular beds [179, 180] including in the cerebral circulation [181–183]. This increase in constriction may be due to both a decrease in buffering capacity from endothelial dysfunction and alterations in the vascular smooth muscle itself [183, 184]. Endothelial dysfunction also has implication for shear-induced dilation since it is highly dependent on NO bioavailability which has consistently been shown to be reduced in MetS. The chronic inflammatory state seen in MetS likely contributes to the reduction in NO bioavailability due to increased scavenging to the produced NO by reactive oxygen species since this reduction in NO bioavailability is consistently reported to evolve in parallel with oxidant stress and the development of a chronic inflammatory state [185, 186]. This is supported by improved dilatory reactivity of MCA with the pretreatment of the cell-permeable superoxide dismutase mimetic TEMPOL in a model of T2DM [145]. Interestingly some studies have actually shown an increase in eNOS expression which may be an attempt to compensate for the increased scavenging; however, they too continue to find reduced dilator reactivity [187].

Aside from reduced NO bioavailability, a shift in arachidonic acid metabolism toward constrictors and away from dilators that are highly responsible for hypoxic dilation has been demonstrated [145]. Thus not only does endothelial dysfunction seen in MetS increase cerebrovascular resistance by decreased dilator metabolite production it may also promote the production of constrictors that exacerbate the impaired dilation capacity of cerebral vessels [184, 188]. A change in sensitivity to various metabolites in addition to their differential production may also contribute to differential vasomotor responses. For example, studies using SNP, an exogenous NO donor, while blocking endogenous NO production by eNOS using L-NAME, found smaller relaxation of the MCA in spontaneously hypertensive rats which was attributed to a decreased expression of soluble guanylate cyclase [189–192]. In a model of T2DM decreased sensitivity of MCA to the PGI2 analog iloprost was also found suggesting that both decrease production and sensitivity of dilators may be contributing to the impaired dilation of the cerebral circulation in MetS [145].

Impaired dilation in response to exogenous dilator metabolites may also be due to vascular remodeling. Structural changes are an important consideration since even if the smooth muscle of a cerebral vessel is able to relax due to metabolic influences resulting in hyperpolarization, remodeling may prevent an increase in lumen diameter which is ultimately the major contributor to acute changes in resistance and thus the regulator of flow. Hypertension is largely implicated in the thickening of the vascular smooth muscle as well as increasing the ratio of collagen to elastin in the vessel. High intraluminal pressure increases the shear stress exerted on the vascular endothelium which normally could be restored to baseline by NO-induced vasodilation [193–195]; however, in a disease state with impaired NO production, there is a reduced ability to dilate resulting in endothelial damage and upregulation of atherogenic genes [193–195]. As a means of protection from chronic increased shear stress and wall tension that may lead to downstream edema cerebral vessels tend to hypertrophy with chronic hypertension, but this protective hypertrophy is also detrimental [188]. Since wall tension is equal to intraluminal pressure X radius and wall stress is wall tension/wall thickness, hypertension-induced hypertrophy and inward remodeling resulting in a decrease in radius and increase wall thickness can normalize both the wall tension and wall stress [188]. Although this remodeling may be protective in regards to increases in pressures and protecting the downstream capillaries from edema it increases the cerebrovascular resistance and limits the dilation reserve during hypotension and therefore presents

**33**

**Figure 2.**

*Cerebral Vascular Tone Regulation: Integration and Impact of Disease*

mises flow to cerebral tissue resulting in hypoxic areas [43].

itself as a right-shift in the autoregulatory range [196, 197]. The development of myogenic tone at higher pressure implies an increased lower limit of autoregulation. This predisposes cerebral tissue to reduced blood flow during hypotension. When pressure drops below the lower limit flow becomes dependent on the passive diameter of the vessel. Not only does an impaired lower limit predispose hypertensive individuals to ischemia but the reduced passive diameter from vascular remodeling further compro-

In addition to hypertrophy and inward remodeling, there is substantial arterial stiffening commonly seen in MetS. The pro-oxidant stress of ROS may interact with components of the perivascular matrix and initiate collagen cross-linking and deposition as well as the breakdown of elastin making the vessel less distensible [198]. This is measured by a left shift in the stress-strain curve of isolated cerebral vessels under passive conditions achieved by using a Ca2+ free solution preventing the development of tone [183]. The stiffening vessel from increased collagen to elastin ratio is made worse by the thickening of vessel walls previously discussed. In a model of T2DM with hypertension significant collagen deposition in addition to medial hypertrophy increasing the wall the lumen ratio and stiffness of the rats MCA [199] was demonstrated while T2DM in the absence of hypertension does not appear to induce structural changes to the cerebral vasculature [145]. This along with data that suggests the increase in arterial stiffness seems to follow a time course similar to that of the onset of hypertension suggests a strong relationship between hypertension and vascular remodeling [200]. Chronic uncontrolled hyperglycemia and inflammation do tend to lead to the development of hypertension and thus contribute to changes in the composition of cerebral vessels and it is likely the combination of both seen in MetS increases the degree to which remodeling occurs. A summary of the impact of disease states on the regulation of cerebral vascular

*A schematic representation of how the presence of metabolic syndrome and the major constituent pathologies* 

*can impact the integrated regulation of cerebral vascular tone.*

*DOI: http://dx.doi.org/10.5772/intechopen.90404*

tone is presented in **Figure 2**.

### *Cerebral Vascular Tone Regulation: Integration and Impact of Disease DOI: http://dx.doi.org/10.5772/intechopen.90404*

*Basic and Clinical Understanding of Microcirculation*

which promote a pro-inflammatory pro-oxidant state. Functionally, MetS is highly linked to increased smooth muscle activation and endothelial dysfunction which has important implications for the ability of a vessel to dilate in response to a multitude of stimuli previously discussed including hypotension, shear, hypoxia, and other metabolic stimuli. Increased myogenic properties are consistently overserved in MetS in multiple vascular beds [179, 180] including in the cerebral circulation [181–183]. This increase in constriction may be due to both a decrease in buffering capacity from endothelial dysfunction and alterations in the vascular smooth muscle itself [183, 184]. Endothelial dysfunction also has implication for shear-induced dilation since it is highly dependent on NO bioavailability which has consistently been shown to be reduced in MetS. The chronic inflammatory state seen in MetS likely contributes to the reduction in NO bioavailability due to increased scavenging to the produced NO by reactive oxygen species since this reduction in NO bioavailability is consistently reported to evolve in parallel with oxidant stress and the development of a chronic inflammatory state [185, 186]. This is supported by improved dilatory reactivity of MCA with the pretreatment of the cell-permeable superoxide dismutase mimetic TEMPOL in a model of T2DM [145]. Interestingly some studies have actually shown an increase in eNOS expression which may be an attempt to compensate for the increased scavenging;

however, they too continue to find reduced dilator reactivity [187].

Aside from reduced NO bioavailability, a shift in arachidonic acid metabolism toward constrictors and away from dilators that are highly responsible for hypoxic dilation has been demonstrated [145]. Thus not only does endothelial dysfunction seen in MetS increase cerebrovascular resistance by decreased dilator metabolite production it may also promote the production of constrictors that exacerbate the impaired dilation capacity of cerebral vessels [184, 188]. A change in sensitivity to various metabolites in addition to their differential production may also contribute to differential vasomotor responses. For example, studies using SNP, an exogenous NO donor, while blocking endogenous NO production by eNOS using L-NAME, found smaller relaxation of the MCA in spontaneously hypertensive rats which was attributed to a decreased expression of soluble guanylate cyclase [189–192]. In a model of T2DM decreased sensitivity of MCA to the PGI2 analog iloprost was also found suggesting that both decrease production and sensitivity of dilators may be contributing to the impaired dilation of the cerebral circulation in MetS [145]. Impaired dilation in response to exogenous dilator metabolites may also be due to vascular remodeling. Structural changes are an important consideration since even if the smooth muscle of a cerebral vessel is able to relax due to metabolic influences resulting in hyperpolarization, remodeling may prevent an increase in lumen diameter which is ultimately the major contributor to acute changes in resistance and thus the regulator of flow. Hypertension is largely implicated in the thickening of the vascular smooth muscle as well as increasing the ratio of collagen to elastin in the vessel. High intraluminal pressure increases the shear stress exerted on the vascular endothelium which normally could be restored to baseline by NO-induced vasodilation [193–195]; however, in a disease state with impaired NO production, there is a reduced ability to dilate resulting in endothelial damage and upregulation of atherogenic genes [193–195]. As a means of protection from chronic increased shear stress and wall tension that may lead to downstream edema cerebral vessels tend to hypertrophy with chronic hypertension, but this protective hypertrophy is also detrimental [188]. Since wall tension is equal to intraluminal pressure X radius and wall stress is wall tension/wall thickness, hypertension-induced hypertrophy and inward remodeling resulting in a decrease in radius and increase wall thickness can normalize both the wall tension and wall stress [188]. Although this remodeling may be protective in regards to increases in pressures and protecting the downstream capillaries from edema it increases the cerebrovascular resistance and limits the dilation reserve during hypotension and therefore presents

**32**

itself as a right-shift in the autoregulatory range [196, 197]. The development of myogenic tone at higher pressure implies an increased lower limit of autoregulation. This predisposes cerebral tissue to reduced blood flow during hypotension. When pressure drops below the lower limit flow becomes dependent on the passive diameter of the vessel. Not only does an impaired lower limit predispose hypertensive individuals to ischemia but the reduced passive diameter from vascular remodeling further compromises flow to cerebral tissue resulting in hypoxic areas [43].

In addition to hypertrophy and inward remodeling, there is substantial arterial stiffening commonly seen in MetS. The pro-oxidant stress of ROS may interact with components of the perivascular matrix and initiate collagen cross-linking and deposition as well as the breakdown of elastin making the vessel less distensible [198]. This is measured by a left shift in the stress-strain curve of isolated cerebral vessels under passive conditions achieved by using a Ca2+ free solution preventing the development of tone [183]. The stiffening vessel from increased collagen to elastin ratio is made worse by the thickening of vessel walls previously discussed. In a model of T2DM with hypertension significant collagen deposition in addition to medial hypertrophy increasing the wall the lumen ratio and stiffness of the rats MCA [199] was demonstrated while T2DM in the absence of hypertension does not appear to induce structural changes to the cerebral vasculature [145]. This along with data that suggests the increase in arterial stiffness seems to follow a time course similar to that of the onset of hypertension suggests a strong relationship between hypertension and vascular remodeling [200]. Chronic uncontrolled hyperglycemia and inflammation do tend to lead to the development of hypertension and thus contribute to changes in the composition of cerebral vessels and it is likely the combination of both seen in MetS increases the degree to which remodeling occurs. A summary of the impact of disease states on the regulation of cerebral vascular tone is presented in **Figure 2**.

#### **Figure 2.**

*A schematic representation of how the presence of metabolic syndrome and the major constituent pathologies can impact the integrated regulation of cerebral vascular tone.*
