|Year : 2015 | Volume
| Issue : 1 | Page : 53-62
The role of shear stress and arteriogenesis in maintaining vascular homeostasis and preventing cerebral atherosclerosis
David Della-Morte1, Tatjana Rundek2
1 Department of Neurology, University of Miami, Miller School of Medicine, Miami, Florida, USA; Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata; Interinstitutional Multidisciplinary Biobank (BioBIM), IRCCS San Raffaele Pisana, Rome, Italy
2 Department of Neurology, University of Miami, Miller School of Medicine, Miami, Florida, USA
|Date of Submission||29-Mar-2015|
|Date of Acceptance||25-Jun-2015|
|Date of Web Publication||30-Sep-2015|
Department of Neurology, Miller School of Medicine, University of Miami, Clinical Research Building, CRB 1348, 1120 NW 14th Street, Miami, Florida - 33136
Source of Support: None, Conflict of Interest: None
Shear stress (SS) is a biomechanical force that is determined by blood flow, vessel geometry, and fluid viscosity. Although a wide range of known vascular risk factors promote development of atherosclerosis, atherosclerotic changes occur predominately at specific sites within the arterial tree, suggesting a critical role for local factors within the vasculature. Atherosclerotic lesions develop predominantly at branches, bends, and bifurcations in the arterial tree because these sites are exposed to low or disturbed blood flow and low SS. Low SS predisposes arteries to atherosclerosis by causing endothelial dysfunction. A natural system of preexisting cerebral collateral arteries protects against ischemia by bypassing sites of arterial occlusion through a mechanism of arteriogenesis. The main trigger for arteriogenesis is impaired vascular homeostasis (VH) in response to local changes in SS induced by ischemia. VH is a critical process for maintaining the physiological function of cerebral circulation. It is regulated through a complex biological system of blood flow hemodynamic and physiological responses to flow changes. Restoration of VH by increasing arteriogenesis and SS may provide a novel therapeutic target for stroke, especially in the elderly, who are more prone to VH impairment. In this review article, we discuss the mechanisms and structures necessary to maintain VH in brain circulation, the role of SS, and risk factors leading to atherosclerosis, including the effects of aging. We also discuss arteriogenesis as an adaptive and protective process in response to ischemic injury, the imaging techniques currently available to evaluate arterogenesis such as magnetic resonance imaging/positron emission tomography (MRI/PET), and the potential therapeutic approaches against ischemic injury that target arteriogenesis.
Keywords: Aging, arteriogenesis, atherosclerosis, cerebral blood flow, cerebral imaging, shear stress (SS), vascular homeostasis (VH)
|How to cite this article:|
Della-Morte D, Rundek T. The role of shear stress and arteriogenesis in maintaining vascular homeostasis and preventing cerebral atherosclerosis. Brain Circ 2015;1:53-62
|How to cite this URL:|
Della-Morte D, Rundek T. The role of shear stress and arteriogenesis in maintaining vascular homeostasis and preventing cerebral atherosclerosis. Brain Circ [serial online] 2015 [cited 2022 May 28];1:53-62. Available from: http://www.braincirculation.org/text.asp?2015/1/1/53/164993
| Introduction|| |
Shear stress (SS) is defined as a biomechanical force that is determined by blood flow, vessel geometry, and fluid viscosity.  This force is a critical factor in maintaining endothelial function and varies with time, magnitude, and direction of blood flow, vascular pulsatility, and anatomy. Relatively straight, unbranched arteries are exposed to uniform, unidirectional flow and experience relatively high SS. In contrast, at vessel bifurcations and bends, the flow is disturbed and it changes directions during the cardiac cycle, resulting in relatively low and oscillatory SS.  Hemodynamic SS as the frictional force acting on vascular endothelial cells (ECs) is crucial for vascular homeostasis (VH). Lower SS predisposes vessels to damage by contributing to endothelial dysfunction and the development of atherosclerotic lesion, whereas high-shear areas may be protected against atherosclerosis by the enhancement of endothelial protection.
VH is required to maintain the physiological cerebral circulation to meet the brain's metabolic demands. The word "homeostasis" can be defined as "the maintenance of metabolic equilibrium within an organ by a tendency to compensate for disrupting changes."  In fact, VH represents the balance between vascular injury and vascular repair. Several biological mechanisms and anatomical structures such as endothelium and smooth muscle cells along with blood flow hemodynamic regulation actively participate to preserve VH. Exogenous and endogenous pathological insults, which increase exponentially with age,  may alter this VH equilibrium. In vascular injury occurring as a result of biochemical or mechanical forces (e.g., in hypertension), normal homeostatic mechanisms are perturbed, and the vessel wall becomes dysfunctional if compensatory mechanisms are overwhelmed. These processes are characterized by changes in regulatory molecules that stimulate aberrant responses, leading to stroke and cardiovascular disease (CVD).  Recent advances in molecular biology including gene technology and novel diagnostic procedures have increased our knowledge of these biological mechanisms and therefore our ability to prevent noxious factors and restore VH. In the present review, we discuss the link between SS and VH in brain circulation, pathological processes, and risk factors leading to atherosclerosis, including the effects of aging. Moreover, we discuss arteriogenesis as an adaptive and protective process in response to ischemic injury, the neuroimaging techniques currently available to evaluate arteriogenesis, and the novel therapeutic approaches against ischemic injury that target arteriogenesis.
| Role of SS and Ecs in Vh and Atherosclerosis|| |
Atherosclerosis is a chronic inflammatory disease in which inflammatory cells, lipids, and extracellular matrix accumulate within the artery wall to form plaques that reduce and may eventually obstruct blood flow, with devastating consequences for the supplying tissues.  Hypertension, hypercholesterolemia, smoking, diabetes, hyperhomocysteinemia, aging, obesity, and genetic predisposition are major risk factors for the development of atherosclerosis. Recent studies conducted in the Northern Manhattan Study (NOMAS) demonstrated that variation in preclinical markers of atherosclerosis, such as carotid plaque and carotid intima media thickness (cIMT), is largely unexplained by both traditional and less traditional vascular risk factors, suggesting that other unaccounted-for environmental and genetic factors play an important role in the determination of atherosclerosis. , Atherosclerotic lesions and plaque formation occur predominately at specific sites within the arterial tree, suggesting a critical role of local factors within the vasculature. In fact, atherosclerotic lesions develop predominantly at branches, bends, and bifurcations in the arterial tree because these sites are exposed to low or disturbed blood flow [Figure 1].
|Figure 1: Risk for atherosclerosis increases at vascular sites of turbulent blood flow. Decreased SS may affect EC response by modulating several biological factors. In the presence of vascular risk factors, some of which are listed in the figure, there is an increased likelihood of atherosclerotic plaque formation at these sites|
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The first indication that sites of atherosclerotic lesion were associated with regions of altered blood flow was published in 1969.  Two main hypotheses emerged to explain this effect: The mass transport theory and the SS theory of atherosclerosis. The mass transport theory is based on the evidence that accumulation of atheromatous material at sites of low or disturbed blood flow with increase rate of uptake of bioactive substances such as low-density lipoprotein (LDL) cholesterol, oxygen, and nitric oxide (NO) from the blood stream into the vessel wall, resulting in an increased length of time the blood stays in contact with the vessel wall in areas of flow stagnation. This hypothesis has been supported by experimental studies by Weinberg et al. that have clearly demonstrated greater uptake of labeled molecules such as LDL and albumin in regions of low blood flow that are susceptible to the development of atherosclerosis.  The SS theory is based on the evidence that the atherosclerotic plaques are more prevalent in the vascular sites when the blood flow is disturbed or is nonlaminar.
Blood vessels are active organs with a variety of functions that maintain the homeostasis of the circulatory system. Vascular functions are controlled by several biochemical mediators, including hormones, cytokines, and neurotransmitters. Biomechanical forces generated by blood flow and blood pressure also play an important role in vascular functions.  ECs are constantly under forces generated by blood flow SS. ECs actively respond to flow stress by modifying their morphology, function, and gene expression.  The responses of ECs to SS include activation of multiple signal transduction pathways such as membrane proteins, ion channels, G protein, and tyrosine kinase receptors, among others,  which are identified as SS-responsive elements (SSREs). However, the exact mechanisms of SS transduction mediated by the ECs are not fully understood. An inadequate EC response to SS plays a critical role in triggering angiogenesis, vascular remodeling,  and atherosclerosis. 
In vitro experiments in which cultured ECs have been subjected to controlled levels of SS in fluid-dynamically designed flow-loading devices demonstrated a morphological change in ECs linked with cellular cytoskeletal reorganization where actin filaments become rearranged into bundles of stress fibers and are aligned in the direction of the SS. , Moreover, ECs in response to SS have been found to enhance NO production via activation of endothelial NO synthase (eNOS) and upregulation of its gene expression.  NO is pivotal in regulating vasodilatation when blood flow increases, and therefore it plays a fundamental role in maintaining cerebral VH.  The release of NO by ECs results in an increase in transcription factors that involves nuclear factor-kappa B (NF-κB) and other SSREs such as prostacyclin, C-type natriuretic peptide, and adrenomedulin, leading to vasodilation. 
Other important mechanisms regulated by ECs in response to SS to maintain VH include release of a variety of growth factors and cytokines,  vascular cell adhesion molecule-1 (VCAM-1),  and control of reactive oxygen species (ROS) production.  Increases in blood flow trigger vascular free radical generation; such a response seems to involve endothelium-derived superoxide radicals unrelated to cyclooxygenase or eNOS activities.  Recent evidences showed a new role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent ROS production in the SS mediated vascular damage.  However, more recent, better characterized NADPH oxidase inhibitors were not considered; therefore, further studies are needed to clarify this interaction that may be important in the development of antioxidant therapy for atherosclerosis.
The maintenance of a physiologic, laminar SS is crucial for normal vascular functioning, which includes the regulation of vascular caliber as well as inhibition of proliferation, oxidation, and inflammation of the vessel wall. Nonlaminar blood flow results in changes to endothelial response, gene expression, cytoskeletal arrangement, and leukocyte adhesion, which lead to vessel damage and atherosclerosis [Figure 2]. A decrease in SS (<5 dynes/cm 2 ) induces atherosclerosis by a direct reduction in endothelial eNOS production, vasoconstriction and decreased EC repair. Impairment in wall vessel function is also coupled with increases in ROS production, endothelial permeability to lipoproteins, leukocyte adhesion, apoptosis, smooth muscle cell proliferation, and collagen deposition.  All major vascular risk factors such as diabetes, smoking, hypertension, and hyperlipidemia, even if we demonstrated them to be limited, , have a direct effect in an additive fashion in both reduced flow-mediated vasodilatation and increased endothelial damage during the progression of atherosclerosis. 
|Figure 2: Schematic diagram of the pathways by which SS may regulate atherogenesis through EC response|
The pathogenesis of the atherosclerotic plaque is modulated by SS regulation of atheroprotective and atherogenic influences by systemic and genetic factors that affect cellular processes in the vessel wall as the response to SS
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Different genetic expression patterns of endothelial genes are up- or downregulated in response to laminar or disturbed flow.  Many of the genes altered by disturbed flow are involved in key biological processes relevant to atherosclerosis such as inflammation, cell cycle control, apoptosis, thrombosis and oxidative stress, suggesting that the presence of low shear and non-laminar flow are sufficient to induce a gene expression profile that pre-disposes the endothelium to the initiation of atherosclerotic lesions.  Most important genes reported to be expressed by ECs under SS stimulus in physiological condition are listed in [Table 1]. All reported genetic patterns are expressed in an inverse way in response to lower SS.
|Table 1: EC genetic expression regulated by SS under physiological conditions|
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SS also plays an important role in the regulation of inflammatory processes that are crucial to initiate and enhance the growth of atherosclerotic plaque. SS greatly influences vascular inflammation by modification of endothelial gene expression to a proatherogenic profile.  In addition, SS controls inflammation by activating peroxisome proliferator-activated receptor gamma (PPARγ) ligands through the PLA2-CYP450 pathway in ECs.  However, interaction between SS, ECs, and inflammation in the atherosclerotic process seems to be strongly dependent on the modulation of proinflammatory cytokine tumor necrosis factor-alpha (TNFα), along with intercellular adhesion molecule-1 (ICAM-1), vascular smooth muscle cells-1 (VSMCs), and E-selectin, which are mediators of inflammation necessary to create the biological environment where the plaque grows. 
Similar to inflammation, dysfunctional SS and endothelium response may increase risk for atherosclerosis by impairing production of NO. NO is protective against atherosclerosis by enhancing vascular relaxation, inhibition of platelet activation and aggregation, and reduction in apoptosis.  Attenuation of NO is one of the earliest biochemical changes of endothelial dysfunction. A large meta-analysis of 26 studies involving 23,028 subjects clearly demonstrated that common genetic variations in eNOS gene and consequent NO availability constitute a significant risk factor for development of atherosclerosis and CVD.  In vascular regions with disturbed blood flow and impaired endothelial-dependent vasodilatation, endothelium overlying atherosclerotic plaques shows a decrease in eNOS mRNA and protein expression. 
SS and endothelium modulate the redox state of the vascular wall mainly by regulating expression of the oxidase systems. The association between ROS production and atherosclerosis is now well established by several experimental and clinical studies.  A chronic exposure of ECs to oscillatory SS increases monocyte adhesion, which is dependent on NAD(P)H oxidase activity  and a mechanism leading to plaque formation. Moreover, SS by itself promotes regulation in antioxidative systems. For example, intracellular glutathione, which is protective against cellular oxidation, is decreased under nonlaminar flow,  while the enzyme glutathione peroxidase is upregulated under laminar flow condition.  Another important mechanism by which lower SS leads to atherosclerosis entails regulating vascular wall permeability by affecting the endothelial cytoskeleton.  Intensive research is currently ongoing to fully understand the role of SS and endothelium response in both physiologic and pathophysiologic vascular biology. Recent findings have indicated that atherosclerotic plaques may also form in arterial sites that have relatively steady SS.  These data suggest that alteration in SS alone may not be the only factor inducing atherosclerosis. Additional hemodynamic factors such as circumferential stress waves other than SS may also contribute to the development of atherosclerosis. 
| The Link Between SS and Arteriogenesis|| |
It is well established that a natural system of preexisting cerebral collateral arteries exists and may bypass sites of arterial occlusion. The major processes by which blood vessels are formed and remodeled in response to ischemic stimuli are vasculogenesis, angiogenesis, and arteriogenesis. , Specifically, arteriogenesis refers to the remodeling of an existing artery to increase its luminal diameter in response to increased blood flow.  While vasculogenesis and angiogenesis are induced by hypoxia and results in the formation of new capillaries, arteriogenesis is induced by physical forces, most importantly blood flow SS. One of the initial triggers for arteriogenesis is an alteration of VH due to altered SS, which appears within the collateral arteriole after an increase in blood flow.  The latter processes of arteriogenesis are induced by the large pressure difference in the preexisting arterioles connecting upstream with downstream branches as the result of an arterial occlusion. Investigations of mRNA expression in tissue derived from the rabbit ischemic hind limb model have shown that arteriogenesis is induced independently of the presence of hypoxia. 
Arteriogenesis has been demonstrated in the brain circulation by using different experimental animal models of cerebral ischemia/reperfusion injury.  An enhancement of the growth of functional blood vessels has been essential for the restoration of blood flow to the ischemic brain and linked to improved functional outcomes after stroke, as experiments noninvasively visualized differential hemodynamic and biochemical processes within the core and perifocal penumbra after ischemia,  demonstrating a high chance of recovery in this surviving region. However, the mechanism underlying ischemia-induced arteriogenesis has not been fully elucidated in the brain. A study conducted in transgenic mice demonstrated that increased eNOS plays an important role in the regulation of arteriogenesis after stroke induced by middle cerebral artery occlusion (MCAo).  The activity of eNOS seems to be essential for neovascularization and arteriogenesis, and is an important adaptive process of the preexisting vessel network for establishing functional VH after stenosis or occlusion.
Increased blood pressure (BP), which follows ischemia/reperfusion injury in the brain, has been identified as the main factor leading to the changes in predominant flow forces in the vessels, such as longitudinal, circumferential, and radial wall stresses. Circumferential wall stress increased by elevated BP triggers proliferation of vascular smooth muscle cells-1 (VSMCs) within the collateral network and contributes to the remodeling process.  However, lower SS has been identified as a major candidate in developing arteriogenesis.  The reduction of SS normally caused by increasing diameters of the growing collateral vessels is most likely responsible for the untimely termination of collateral growth.  As discussed above, the primary physiological response in SS-induced arteriogenesis is an activation of ECs. Regulation of gene expressions from ECs under SS encode for chemoattractant, activating cytokines and adhesion molecules. Among those, the monocyte chemoattractant protein-1 (MCP-1) has been shown to play an essential role in arteriogenesis. An increase of this chemotactic gradient by chronic local infusion of MCP-1 in rabbits markedly enhanced arteriogenesis in a model of femoral artery occlusion.  Other factors such as ICAM-1 and -2 and VCAM-1 have been also demonstrated to be involved with the growth of collateral circulation under SS reduction stimulus.  Mice with a genetic deficiency of the T-cell marker CD4 (CD4 -/- ), showed inhibition of arteriogenesis in a model of hind limb ischemia, which could be repaired by an injection of purified CD4-positive cells, supporting the role of inflammatory and immune response in arteriogenesis.  Further experiments also showed that expression of interleukin 16 (IL-16) was essential in the modulation of collateral development in response to ischemia. 
Recently, the role of stem cells or progenitors incorporated into the walls of growing blood vessels have been investigated in arteriogenesis, predominately as components of the endothelium or VSMC vessel layers. Multiple animal species such as mice, rats, and rabbits and different cell populations such as mononuclear fraction of bone marrow cells and progenitors isolated from blood have been tested in preclinical studies.  The results from these studies have been controversial and the biological mechanisms of arteriogenesis in these models have not been yet elucidated. Further studies are imperative to better understand the role of stem cells in arteriogenesis and their therapeutic use to restore VH.
| Aged-Related Reduction in SS and Increased Risk of Atherosclerosis|| |
Aging is defined by a progressive functional decline of an intrinsic, inevitable, and irreversible age-related process of loss of viability and increase in vulnerability.  Therefore, the result of aging is a progressive reduction of whole-body homeostasis including cerebral VH, with an increasing risk for stroke and CVD. In fact, CVD and stroke account for more than of 85% of death in patients older than 65 years.  Several risk factors contribute to the high risk of CVD mortality in the elderly, including hypertension, hyperlipidemia and diabetes, age-related prothrombotic changes in the hemostatic system, cardiac disease, and the presence of other comorbidities. 
Age-associated arterial changes in apparently healthy humans include luminal dilation, increase in arterial stiffness, endothelial dysfunction, and diffuse intimal thickening.  These changes determine an alteration in the regulation of arterial properties, including vascular tone, vascular permeability, angiogenesis, and the response to oxidative damage and inflammation. All of these factors lead to a dramatically increase in risk for atherosclerosis in the elderly. A clinical study conducted in children, adults, and elderly subjects showed that atherosclerosis was 6- to 19-fold greater in aged compared to younger subjects. Antioxidant enzymes appear to play a role in these age-dependent differences. 
Cerebral autoregulation seems to become impaired and cerebral blood flow (CBF) is gradually reduced with aging.  A meta-analysis reported no evidence of impaired cerebral autoregulation in healthy subjects aged 50-75 years.  However, comorbidity typical of elderly subjects altered cerebral autoregulation, especially in the oldest patients.  In aged vessels, an alteration of SS with an impaired response of ECs has been demonstrated and termed EC senescence [Figure 3].  Clinical studies have demonstrated that mean SS is significantly lowered in older compared to younger subjects. Age-related reduction in SS leads to a decrease in NO production and bioavailability, resulting in VH reduction in elderly patients.  Compared with ECs isolated from young subjects, ECs from the elderly displayed an impaired migration and adhesion in vitro and demonstrated a significantly reduced re-endothelialization capacity in vivo after transplantation into nude mice with carotid artery denudation injury.  However, normal SS pretreatment (15 dyne/cm 2) enhances the migration, adhesion, and re-endothelialization capacity in both young and elderly ECs. This treatment suggests the possibility that restoring VH may improve the capacity to response to injury in vascular aging.  An aged brain is not only more predisposed to ischemia but also more susceptible to ischemic damage  compared to a younger brain.
|Figure 3: Schematic diagram of the pathways by which aging may lead to atherosclerosis and CVD through reduction of VH|
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An experimental study conducted in 3- and 24-month-old rats exposed to high blood flow and normal blood flow showed that flow remodeling in resistance arteries failed to occur in aged compared to young animals, suggesting a different response of older vessels to the conditions associated with flow-dependent remodeling such as ischemic and metabolic diseases.  A study investigating the relationship between age and arteriogenesis in C57/BL6 mice following the carotid artery occlusion model of ischemia demonstrated that baseline perfusion in sham surgery and cerebrovascular reactivity after artery occlusion were significantly lower in animals aged 18 months compared with mice aged 4-6 weeks and 12 weeks.  Taken together, these findings strongly suggest that arteriogenesis is impaired with older age, which may result in susceptibility to hemodynamic stroke or inadequate response to ischemia in the elderly.
| SS and Arteriogenesis as Potential Therapeutic Targets Against Cerebral Ischemia|| |
The augmentation of vascular growth and consequently blood flow for the treatment of patients with ischemic insult is a potential strategy. As arteriogenesis can potentially be triggered by alteration in SS, the main strategy is to manipulate SS in cerebral areas of new vessel growth. An experimental study conducted in rats has demonstrated that increase in SS induced by bilateral carotid ligature followed by creation of a unilateral arteriovenous fistula enhances arteriogenesis measured by magnetic resonance angiography (MRA).  This phenomenon seems to be dependent on SS-sensitive calcium channels Trpc1, Trpm7, Trpp2, Trpv2 (transient receptor potential cation channel, subfamily V, member 2), and Trpv4, suggesting that the pharmacological activation of these channels may be a possible new therapeutic approach for stroke.  Several other factors have been found to accelerate or augment collateral artery growth in animal models including vascular endothelial growth factor (VEGF), transforming growth factor-β, platelet-derived growth factor-BB, heparin, angiopoietin 1, the chemokine MCP-1, and granulocyte-macrophage colony-stimulating factor among others.  Thus pharmacological manipulation of each of these factors for their increase in arteriogenesis may be potentially used in patients after cerebral ischemia. However, arteriogenesis may have some limitations. Recently, LaManna et al.  reported that the optimal continuous supply of oxygen and nutrients to the brain, even after stroke, is maintained by a dynamic microvascular remodeling, which is a balance between factors secreted during hypoxia, such as COX-2 and Ang-2, and regression of microvessels.
Recently, interest has been focused on the potential role of stem cells and gene therapy in enhancing arteriogenesis after ischemia. Novel findings suggest that human neural stem cells (hNSCs) delivered on poly(D,L-lactic acid-co-glycolic acid) (PLGA) microparticles increase neovasculature after cerebral ischemic injury in rats independently of VEGF, suggesting that stem cells may be involved not only in tissue repair but also in the development of collateral circulation after tissue damage.  Induced arteriogenesis using a three-vessel occlusion rat model of nonischemic cerebral hypoperfusion has shown a significant deregulation of 164 genes 24 h after ischemic insult. Expression patterns have contained gene transcripts predominantly involved in proliferation, inflammation, and migration. Analysis of molecular annotations and networks associated with differentially expressed genes has revealed that early-phase cerebral arteriogenesis was mainly characterized by the expression of protease inhibitors.  Each of these genetic patterns expressed in the early phase of cerebral arteriogenesis may be designated as a molecular marker for gene therapy after stroke.
Novel findings have indicated that acetylsalicylic acid, but not clopidogrel, inhibits therapeutically augmented cerebral arteriogenesis in rats after ischemia.  Similarly, vitamin E supplementation induces arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuates the activity of matrix metalloproteinase-2 in the canine ischemic brain  as well as supplementation with Niaspan (a prolonged-release formulation of niacin) in the rat brain.  In addition, rats treated with simvastatin (1 mg/kg) 7 days before stroke onset had increased arteriogenesis after cerebral ischemia.  However, no human clinical trial currently tests these compounds for arteriogenesis after stroke. Most clinical trials using the arteriogenesis and angiogenesis approaches have been conducted after limb and heart ischemia, reporting controversial results.  A recent clinical trial aimed to increase collateral circulation by using the NeuroFlo™ catheter designed to partially obstruct the abdominal descending aorta, thereby increasing CBF to the brain after stroke, was recently withdrawn (www.clinicaltrials.gov).
Ischemia preconditioning (IPC) induced by MCAo in spontaneous hypertensive rats has demonstrated protection against lethal brain ischemia by increasing arteriogenesis and by activating various molecular pathways involving mitochondrial metabolism.  These evidences may open new therapeutic horizons. Our group has demonstrated that low doses of resveratrol (3, 5, 4'-trihydroxystilbene), a natural polyphenol found in grapes and wine, protect rat hippocampal neurons against lethal ischemia in the same fashion as IPC via the Sirtuin 1-uncoupling 2 (UCP2) mitochondrial pathway. A role for resveratrol or sirtuin's activators in arteriogenesis has not been established or tested yet in human clinical trials.
Therapeutics that enhance perfusion by collateral circulation outside the ischemic core present a potential novel opportunity for stroke therapy. Further clinical research is imperative to elucidate the role of arteriogenesis in stroke and its potential therapeutic target in acute and chronic ischemia, as well as potential negative effects.
| Cerebral Imaging Evaluation of Novel Vessel Formation|| |
The ability to monitor arteriogenic along with angiogenesis processes, especially after ischemia, has been a long-standing challenge. One of the main issues has been to understand whether collateral development occurs de novo, similar to angiogenesis, or whether it represents remodeling and enlargement of preexisting vascular vessels. During arteriogenesis, novel or reopened arteries can be visualized by angiography.  Therefore, angiography remains the gold standard as the diagnostic procedure to evaluate arteriogenesis, although a difficulty in controlling factors such as vascular tone, amount of the injected contrast, force of injection, and different medications may influence the angiographic appearance of brain vessels. However, refinement of diagnostic techniques for assessment of collateral circulation may facilitate the pathophysiological characterization of these vessels with potential therapeutic and prognostic applications. ,, These techniques include xenon-enhanced computed tomography (CT), single-photon emission CT (SPECT), positron emission tomography (PET), CT angiography (CTA), and MRA.  All of these diagnostic procedures provide information regarding the amount of perfusion to specific regions of the brain. Prolonged transit times of arterial CBF may be indicative of collateral blood supply on perfusion studies. 
Although animal research on collateral circulations is limited by the anatomic differences among species, it is useful for understanding the potential utility of different and novel imaging techniques. By using fluorescence in isothiocyanate microangiography, a study conducted in rats reported acute distension of collateral arterioles to the ischemic penumbra after focal cerebral ischemia induced by MCAo.  Interesting, 30 days later, these vessels had doubled their diameters, increased their segment lengths by about 20%, and had assumed a more tortuous course. There was no de novo formation of collateral vessels, even though some capillary proliferation in the ischemic penumbra. An in vitro study conducted in bovine aortic ECs by using a recently developed flow system capable of changing flow direction to any angle showed that the angle between flow and cell axis, defined by their shape and cytoskeleton, determines EC responses and then arteriogenesis.  A newly developed model of line-scanning particle image velocimetry (LS-PIV) confirmed its utility in blood velocity measurement in live mice.  Another imaging methodology used in rodents to evaluate arteriogenesisis is the three-dimensional δR2-based microscopic MRA (3D δR2-μMRA), which enables high-resolution visualization of cerebral vessels while simultaneously providing functional information on the novel microvasculature. 
In humans, noninvasive techniques have limited resolution in evaluating collateral circulation after ischemia, precluding evaluation of the brain of leptomeningeal and other secondary collateral pathways.  Cerebral vasomotor reactivity testing with transcranial Doppler (TCD) may provide information on autoregulation and collateral status, employing serial evaluation of CBF in response to a vasodilatory stimulus, such as inhalation of a mixture of air and CO 2 , acetazolamide injection, or apnea.  However, these stimuli may have different effects on the CBF hemodynamic, conferring relative advantages and disadvantages in evaluating arteriogenesis, and need to be used with caution if there is a vascular compromise. Correlative studies linking conventional angiography with advanced multimodal CT or MRI techniques have enriched the current understanding of collateral circulation after ischemic insults.  CTA source images may offer valuable information regarding collateral circulation after ischemia,  while MRA can be potentially used in the clinical setting and in animal research to evaluate CBF and collateral circulation after stroke. 
Spatial resolution of SPECT imaging along with PET makes these imaging techniques best suited to evaluate vasculature development after ischemia including vessel growth, improvement in tissue perfusion, or oxygenation. These imaging technologies therefore may not be sensitive enough to measure "small" but important variations in CBF hemodynamics after an ischemic insult, or the hypothesis that arteriogenesis contributes to improvement is not correct. A proposed alternative has been a combination of PET and MRI. This new imaging technology model fuses morphological and biological information allowing the simultaneous acquisition of several parameters including vascular anatomy, tissue metabolites, migration of cells, O 2 consumption, and blood flow.  Integrated PET/MR offers great potential in the field of cerebral imaging and may prove to be a useful tool in brain research on arteriogenesis and angiogenesis.
In summary, the specific advantages and limitations of each imaging technology must be considered for the evaluation of a complex process of arteriogenesis, especially in the relationship with the timing of studies as collateral vessels rapidly evolve after the onset of ischemic event.
| Conclusion|| |
The maintenance of VH appears to be important to prevent atherosclerosis and resulting stroke. Alteration of VH is related to vascular risk factors as well as vascular anatomy. SS and ECs play a fundamental role in this process, although the exact mechanisms are not fully elucidated. The remodeling of preexisting collateral circulation to functional arteries termed arteriogenesis is an important physiological mechanism by which vessels compensate for an occlusion or stenosis of a major artery. An impairment of VH and arteriogenesis has been linked to aging, while restoration of normal blood flow hemodynamic has been shown to exert a protective role in aged vessels against ischemic damage. Development of new experimental models such as transgenic animals, and the advent of new methodologies able to evaluate gene-expression profiling, the proteomics, and the metabolomics along with novel imaging technologies may help to better understand VH physiology and the mechanisms leading to atherosclerosis and arteriogenesis. The rapid progress of these fields opens new horizons to develop alternative therapeutic strategies to treat and prevent stroke.
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Conflicts of interest
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