The Role of Transient Receptor Potential Channels in the Pathogenesis of Cerebral Aneurysm Formation

    

    

    Figure 1:  Schematic presentation of the role of transient receptor potential channels in the stages of cerebral aneurysm formation.
TNF- Tumor Necrosis Factor, NO - nitric oxide; EDHF - Endothelium-derived hyperpolarizing factor; VEGF - vascular endothelial growth factor; GATA (globin
transcription factor); ROS - reactive oxygen species; ICAM- intercellular adhesion molecule; VCAM - Vascular cell adhesion protein; (+) – stimulation; (+)- inhibition.
    
    

Mechanotransduction of the hemodynamic forces

The shear stress induces increase in Ca²⁺ concentration in cells of the arterial wall through external mechanosensitive Ca²⁺- permeable cation channels, which act as mechanosensors in recognizing alterations of hemodynamic forces [17]. Ca²⁺ sparks are intracellular Ca²⁺ release events that are important in excitation-contraction coupling and arise from the activation of a cluster of ryanodine receptors. These Ca²⁺ sparks activate nearby sarcolemmal voltageand Ca²⁺- activated potassium channels (BK channels) and increase the frequency of macroscopic outward K+ currents [18]. The sheerstress induces oscillations with a complex spatial, temporal and frequency pattern, therefore amplitude of such Ca²⁺ fluctuations modulates the synthesis of endothelial vasodilators depending on the degree of mechanical stimulation [19]. However, there are several pathways associated with lipid bilayer mechanics, specialized forcetransducing structures, biochemical reactions, membrane trafficking and transcriptional regulation, which have been proposed so far [20]. The suggested mechanisms could be divided into direct and indirect ones. The direct mechanism is based on the membrane model, which presumes direct activation, by alteration in the hemodynamic forces, resulting in tension-dependent stimulus transfer between lipids and transmembrane segments of channels. It has been suggested that TRPC1 channel acts according that model [21,22]. TRPC1 and large conductance calcium-activated, potassium-selective channels (K^Ca1.1) can form a physical complex in vascular smooth muscle cells and that complex plays an important role in the smooth muscle hyper polarization and control of vascular tone [23]. However, interestingly, alternative model for TRPC channels has also been proposed. There is a study revealing that a mechanosensitive Gq-coupled receptor could induce the downstream molecular pathway of blood vessel myogenic response [24]. Some of TRPC channels have been shown to be paired with and activated by the Gq-PLC signaling system [25]. Previous reports have found that TRPC6 is not a classical mechanosensitive ion channel itself, but is activated by a mechanical stimulus when co-expressed with the angiotensin receptor 1 (AT1R) [24,26]. Agents that inhibit Gq or PLC suppress mechanical activation of the channel. The competitive AT1R antagonist, losartan, inhibits the Bayliss effect, both in cerebral arteries and in isolated perfused kidney [24]. The data has been validated especially for myogenic responsiveness of anterior cerebral arteries [27]. Thus, it has been concluded that mechanical activation of Gprotein coupled receptor might be the missing link between a mechanical stimulus and activation of TRPC channels [26].

The indirect model called distant force-sensing model involves mechanical stimuli transduction through an intracellular signalling cascade, for example through the phospholipase A2 (PLA2) pathway [28]. In this mode, channels are considered mechanically sensitive, but not mechanically gated. This mechanism has been clearly demonstrated in the case ofTRPV4 channel. This channel can be activated directly, by mechanical stimulation of phospholipase A2, or with PLC pathway and membrane G proteins [29-31]. It has been found that shear-stress-induced vasodilation was diminished by Ruthenium Red, suggesting a role for TRPV4 channel in this response [32]. Similar findings have been confirmed by reports demonstrating an absence of shear-stress-induced vasodilation in carotid arteries isolated from TRPV4-knockoutmice [33,34]. Recent studies suggest that mechanical activation of TRPV4 in arteries by physiologically relevant shear stress and flow/reperfusion is a critical component of endothelial mechanotransduction [33].

Shear stress-induced activation of TRPV4 channels might involve tyrosine phosphorylation, as has been suggested for the channel activation by osmotic stress using heterologous expression model [35]. However, inhibition of protein kinase C and tyrosine kinase does not exert any effect, thus it has been concluded that TRPV4 phosphorylation does not play a major role in the shear stress– induced response [36]. It has been found that under conditions of mechanical stress TRPV4 channel induces NO- (nitric oxide) and EDHF- (endothelium-derived hyperpolarizing factor) dependent mechanisms in carotid arteries of rat and mouse [37]. This action could be explained by a functional linkage between TRPV4 and the calcium-dependent potassium channel that would result in endothelial hyper polarization [38].

Activation of TRPP2 or TRPA1 channels leads to the transduction of mechanical forces through the cytoskeleton [39,40]. TRPP1 that links to TRPP2 to build a functional channel may act as a sensory molecule transducing the hemodynamic stimulus to TRPP2, which then triggers Ca²⁺ sparks [41].

Worth of emphasize is the difference between sheer stress and membrane stretch, because it is not clear whether both activate the same or different channels. There is a study, in which shear stress– activated channel, TRPV4, has been shown to be insensitive to membrane stretch [42]. TRPC1 and TRPV2 are activated by pulsatile stretch, but there is no direct data, which could confirm their respond to shear stress [43].Generally, it has been shown that TRPs activated by stretch include TRPC1 [44] and TRPV2 [45], and on the other hand flow-activated channels are TRPV4 [46] and TRPP1/TRPP2 complex [41]. However, the sensitivity of most stretch-activated Ca^2+- permeable channels to flow shear stress has not been investigated [47]. On the other hand, some findings suggest that Ca^2+- permeable channels can be responsive to both membrane stretch and flow shear stress [48]. This data also has shown that stretch-activation may be the primary pathway underlying flow-induced Ca²⁺ sparks in endothelial cells [43].

Other studies revealed that TRPM7 channels may display mechanosensitive properties. Implication of these findings is that shear stress may induce a translocation of surface TRPM7 to the plasma membrane in vascular myocytes cells in response to high laminar flow or in areas, where endothelial cells have been damaged. TRPM7 activation results in increased influx of Ca²⁺ in damaged cells that subsequently may trigger cell proliferation, support formation of atherosclerotic plaques and finally induce cell death [30,49].

The mechanism of response to shear-stress was reported by Thilo et al. [50]. In the experimental shear stress, to which cultured vascular endothelial cells were exposed, three different hemodynamic conditions were applied: constant laminar flow, laminar pulsatile atheroprotective flow or laminar atheroprone bidirectional flow. It has been determined that depending on chosen mode of flow; TRPC6 and TRPV1 were significantly increased in atheroprone flow profile compared with an atheroprotective one. Similarly, atheroprone flow induced higher expression of TNF-α mRNA, what was correlated with the higher expression of TRPC6, but not TRPV1. Probably, GATA1 (globin transcription factor) and GATA4 regulate TRPC6 expression during the atheroprone shear stress [51]. Although, TRPC6 and TRPV1 channels are overexpressed in the conditions of artheroprone flow, their action on endothelium might be opposite. Activation of TRPV1 channels attenuates atherosclerosis [31], whereas TRPC6 promotes this process. Increased TRPC6 expression in branched arteries leads to vascular endothelial growth factor–mediated endothelial permeability and thrombin-induced endothelial shape change [52].

In another context, shear-stress may contribute to the cerebral arteriogenesis by activation of TRPV4 [53]. Cells of the small capillaries are anchored to the extracellular matrix and blood flow is responsible for cell deformation. Therefore, it has been suggested that shear-stress increases TRPV4 expression in the membrane and induces collateral vessel growth.

Endothelial dysfunction, inflammatory cascade and oxidative stress

Pathological changes of cerebral vessel endothelial cells may be an inciting event in the formation of cerebral aneurysms. Hemodynamic stress exerts a mechanical pressure on the surface of endothelium [30] causing diverse biochemical and physiological reactions in response. Endothelial dysfunction might be observed in certain areas of cerebral arteries, such as branch points that experience variable shear stress and flow reversal [50]. TRP channels, including TRPV4 and the TRPP1–P2 complex, are activated by shear stress [6,53,54]. The dysfunction or dysregulation of these channels may impair flowinduced vascular auto regulation. Kohler et al. have found that Ca²⁺ influx through endothelial TRPV4 channels triggers NO- dependent vasodilatation in endothelium and NO- and EDHF-dependent vasodilatation of small-sized vessels [54].

Malfunction of endothelial TRPP1 and TRPP2 impairs regulation of NO synthase, resulting in endothelial dysfunction, which may contribute to progress of common genetic Autosomal Dominant Polycystic Kidney Disease (ADPKD). Oancea et al. have found that TRPM7 is sensitive to flow shear stress and participates in pathological responses to arterial wall injury [30]. The exposure of vascular muscle cells to shear stress after endothelial injury leads to a significant accumulation of functional TRPM7 channels at the plasma membrane in less than 2 minutes. The rapid time course for this response suggests that TRPM7 is among the first molecules that respond to shear stress [30]. Over activation of TRPM7 after the exposure of vascular smooth muscle cells to flow shear stress facilitates the translocation of TRPM7 proteins to the plasma membrane, which results in an increase in the whole-cell TRPM7 currents. Increased TRPM7 activity may cause smooth muscle cell injury in areas in which smooth muscle cells are exposed to flow, such as in atherosclerotic regions. Under normal physiological conditions endothelial cells that are permanently exposed to higher levels of shear stress may down regulate the response to mechanical stimuli. However, under prominent hemodynamic stress or rupture of atherosclerotic lesion, vascular smooth muscle cells may respond quickly, therefore expressing higher levels of TRPM7. In response to TRPM7 activation intracellular calcium induces smooth muscle proliferation at lower levels and cell death at high levels [30].

High oxidative stress in the arterial wall initiates macrophage infiltration, humoral or cell-mediated inflammatory responses that have a significant role in aneurysm formation mostly by loss of mural cells in its wall [2]. TRPM2, TRPM4, TRPV1, TRPV2 have been functionally described on macrophages and they have a profound impact on monocyte function [3,55]. TRPV2 that is expressed on macrophages may play a critical role in early phagocytosis and points to this channel as an interesting candidate to be explored regarding a potential modulatory role of efferocytic properties of macrophages in atherogenesis [56,57].

Monocyte recruitment to the endothelium entails interaction of integrins on the monocyte surface with intercellular cell adhesion-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). TRPC3 expression is obligatory for ATP-induced VCAM-1 and ICAM-1 monocyte endothelial adhesion [58]. Both ICAM-1 and VCAM-1 have a central function not only in mediating adhesion of monocytes to the endothelial layer, but also in the endothelial intracellular signalling that supports transmigration of the bound monocyte.

TRP channels may potentially act as endothelial cell sensors for oxidative stress. TRPC3 is a component of oxidant-activated cation channels in endothelial cells. Poteser et al. have demonstrated that oxidant-activated TRPC3 cation conductance in TRPC3- overexpressing HEK cells and porcine aortic endothelial cells is inhibited by dominant negative mutants of TRPC4 [59]. TRPM2 and -M7 have an important functional role in oxidative stress-induced cell injury. The role of TRPM2 isoforms in cell proliferation and oxidant-induced cell death has been well established [60].

Structural remodelling of the arterial wall

Hemodynamic stress initiates structural remodelling of arterial wall, smooth muscle cells intensively proliferate and chaotically migrate to the intima (myointimal hyperplasia) [2]. The early stage of the wall remodelling process reflects the repairing mechanism of artery damage after the pathological hemodynamic forces had acted. An intra-luminal thrombus is being infiltrated by Smooth Muscle Cells (SMC), mural cells begin to proliferate and synthesize new collagen matrix [61]. The remodelling process, although complex in nature, is mediated by TRP channels.

TRPC6 and TRPM4, being sensors of mechanotransduction during the myogenic response induced by an increase of intraluminal pressure, are likely candidates as stretch-activated cation channels in vascular smooth muscle [27]. These channels may be directly activated by membrane stretch or by cell-signalling pathways. TRPC6 is activated by pressure-induced smooth muscle depolarization causing vasoconstriction of cerebral resistance arteries. Blocking of TRPC6 expression attenuates membrane depolarization, swellingactivated currents in cerebral myocytes and vasoconstriction induced by elevation of intraluminal pressure. TRPC6 participates in the intravascular pressure-induced depolarization and constriction of small arteries and arterioles known as the Bayliss effect [62].

TRPM4 channel contributes to stretch-induced myogenic depolarization and SMC migration after their prolongated activation in the cerebral arteries [63]. TRPC5 channel does not constrict cerebral arteries, but rather may participate in the process of SMC migration and proliferation [64].

The function of vascular myocytes is regulated by the activity of TRPC1 channel. Overexpression of this channel in cerebral arteries is associated with substantial increase in store-operated Ca²⁺ entry, suggesting that TRPC1 forms store-operated Ca²⁺ influx channels in vascular myocytes [65]. TRPC1 expression is increased during Ang II induced vascular hypertrophy and during vascular occlusive disease [66]. TRPC1 activity is also associated with SMC proliferation that occurs following activation of store-operatedCa²⁺ entry.

It’s presumed that TRPM7 channel mediates pathological alteration in the vascular adventitia and can be activated by stretching or shear stress in vascular SMC. The activation of TRPM7 by pressure overload-induced stretching can recruit macrophages into thickened adventitia and increase remodelling in a mechanosensitive manner. TRPM7 modulates the infiltration of macrophages and acts synergistically to promote collagen accumulation and vascular adventitial formation during pressure overload in rats with TAC (transverse aortic constriction) [55].

Non-physiological hemodynamic forces produce endothelial dysfunction resulting in collagen exposure and thrombus formation [2,67]. Probably the first degenerative change in arterial wall is damage of layer, which leads to the formation of fibrin network and thrombus on the exposed collagen surface. The abnormal Ca²⁺ influx in endothelial cells lacking of TRPC4 channels was associated with a lack of thrombin-mediated actin-stress fiber formation. The inability of thrombin to induce actin-stress fiber formation may be a direct result of TRPC4 interaction with protein 4.1, an endothelial cytoskeletal protein [68]. Thrombin is an inflammatory mediator that activates TRPC1. Both, the resultant Ca²⁺ influx and tumor necrosis factor-alpha stimulate the expression of TRPC1 in human vascular endothelial cells [69]. In response, increased expression of TRPC1 augments Ca²⁺ influx via store-operated channels and potentiates the thrombin-induced increase in permeability in human vascular endothelial cells [70].

The one suggestion implying the linkage between aneurysms etiopathogenesis and TRP channels derives from the study on Autosomal Dominant Polycystic Kidney Disease (ADKPD) [71,72]. ADKPD patients suffer not only from kidney cysts and arterial hypertension, but also form aneurysms as a result of thinning of the vessel wall that facilitates aneurysmal bleeding [73].The link between intracellular Ca²⁺ level alterations and aneurysms is not clear, but the suggestion is that TRPP channels take part in the control of the myoelastic structural integrity of arteries [74]. TRPP2 seems to be especially important for the stability of the vessel wall - the survival time of patients with TRPP2 mutations is longer than for those with TRPP1 defects [75].

TRPP1/TRPP2 complex is highly expressed in arterial smooth muscle cells and there is a likelihood, that mutations in both encoding genes have impact on structural and functional integrity of the arteries [41].The current concept is that the large terminal region of TRPP1 protein may act as a flow sensor modulating the activity of the coupled TRPP2 channel subunit, which activity remains also under the control of tubulin [76]. SAC (Stretch-Activated Channels) currents in smooth muscle cells are suppressed by TRPP2 expression, which is reversed by TRPP1 expression, indicating that TRPP1/TRPP2 expression ratio plays a regulatory role for pressure-induced Ca²⁺ entry SMC [74]. It is noteworthy that TRPP2 associates with TRPC1, but similarly, TRPP2 may also associate with TRPV4 channel [77]. The physiological significance of the TRPC1/ TRPP2and TRPV4/TRPP2 complexes remains to be investigated more precisely. It has recently been proposed that structural changes in microtubule-TRPP2 links may constitute a regulatory mechanism of channel function via the microtubule dependent motor kinesin-2 subunit KIF3A, also involved in the pathogenesis of ADPKD [78]. However, it is still unknown whether the loss of mechanosensation is the direct cause of ADPKD. It is possible that the TRPP complex may fulfill another function, including chemo sensation as recently demonstrated for the PKD1L3/PKD2L1 (TRPP3) complex [79].

Conclusion

In the above mention revision authors presented the role of TRP channels in the pathogenesis of cerebral aneurysms formation. Although the current results and data are based mainly on animal studies, it can be hypothesized that TRP channels allow explaining many unclear issues of cerebrovascular diseases. It seems that there should be paid more attention to TRP channels in clinical studies to confirm previous observations. Definitely, TRP channels are involved in many cerebrovascular processes that are crucial in the physiology of cerebral circulation. Their modulative abilities regulate the adequate blood flow in different hemodynamic conditions. Finally, under the pathological shear stress TRP channels transduce mechanical stimuli that initiate cascade leading to the aneurysm formation. Current knowledge justifies the conclusion that TRP channels play an important role in the process of cerebral aneurysms formation. Therefore, modulation of their activity should be taken into account in future clinical trials on cerebrovascular diseases.

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