Clinical Neurology and Neurosurgery 126 (2014) 126–129

Contents lists available at ScienceDirect

Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro

A hierarchical model for the development of cerebral arteriovenous malformations Wyatt L. Ramey a,b , Nikolay L. Martirosyan b , Joseph M. Zabramski b , Robert F. Spetzler b , M. Yashar S. Kalani b,∗ a b

Division of Neurological Surgery, Department of Surgery, The University of Arizona, Tucson, USA Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, USA

a r t i c l e

i n f o

Article history: Received 8 July 2014 Accepted 24 August 2014 Available online 30 August 2014 Keywords: Arteriovenous malformation Embryology Polymorphism Vasculogenesis

a b s t r a c t Objective: Cerebral arteriovenous malformations (AVMs) are vascular lesions whose pathogenesis, although not fully elucidated, is likely multifactorial. Recent research investigating vessel development suggests a potential hierarchical model in which capillary sprouts from higher-flow arteries give rise to lower-flow veins. It is possible that an embryologic structural vascular dysgenesis in this hierarchical development heavily contributes to the formation of AVMs. Subsequent genetic “second hits” may then allow development of a clinically significant cerebral AVM. We review this vascular developmental process and describe a novel proposal for the embryogenesis of AVMs and its implications in relation to recent research on polymorphisms and AVMs. Methods: A comprehensive literature search was performed using PubMed for recent research relative to cerebral AVMs, embryologic vascular development, and polymorphisms involved in AVM pathology. Results: It has recently been shown that both centrally, in the axial embryo, and peripherally, in the embryonic yolk sac, veins form via capillary sprouting from parent arteries. In developing intracranial vessels, a derangement in this embryonic process may lead to a primitive arteriovenous shunt. After this structural “first hit,” we suggest that single nucleotide polymorphisms (SNPs) are a major component in allowing AVM growth into symptomatic clinical lesions. Conclusions: This is a novel theory for the embryologic formation of cerebral AVMs. Hierarchical vessel development, where higher-flow parent arteries give rise to lower-flow veins, provides a potential mechanism for the formation of primitive arteriovenous shunts that, with the influence of polymorphisms, allows AVMs to develop. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Maturation of the human circulatory system is a complex and fragile process that has its beginnings early in embryogenesis. Soon after fertilization, the rapidly proliferating embryo develops the need for an intrinsic oxygen delivery system. This is why vasculogenesis occurs so early in the development process, and it explains why the cardiovascular system is the first fully functioning organ system [1]. Starting with hematopoiesis and vasculogenesis, the primitive circulatory system coalesces to form the major blood

∗ Corresponding author at: c/o Neuroscience Publications, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, 350W. Thomas Road, Phoenix 85013, USA. Tel.: +1 602 406 3593; fax: +1 602 406 4104. E-mail addresses: [email protected], [email protected] (M.Y.S. Kalani). http://dx.doi.org/10.1016/j.clineuro.2014.08.029 0303-8467/© 2014 Elsevier B.V. All rights reserved.

vessels, which subsequently undergo angiogenesis and differentiation into arteries and veins to form more intricate smaller vessels. Embedded in this process is the potential for numerous pathologies to develop, including intracranial arteriovenous malformations (AVMs), whose molecular biology and physiology is reviewed elsewhere [2,3]. AVMs are dynamic abnormalities—they exhibit increased vascular remodeling and aberrant hemodynamics, which contribute to several pathologic characteristics, such as mass effect, pathologic inflammation, unstable vessel walls, and intracranial hemorrhage. Multiple theories exist regarding the congenital nature of these lesions, including the existence of a developmental proliferative capillaropathy [4], a dysfunction in vascular remodeling at the junction between veins and capillaries [5], and aberrations during a stage of absorption of numerous dural-pial subarachnoid veins [6]. Although the exact pathogenesis of AVMs is yet to be elucidated, it is clear there is a strong genetic component. This genetic

W.L. Ramey et al. / Clinical Neurology and Neurosurgery 126 (2014) 126–129

link is especially strong in AVM patients with known comorbid congenital vascular defects, such as hereditary hemorrhagic telangiectasia and Sturge–Weber syndrome. Newer studies are beginning to identify single nucleotide polymorphisms (SNPs) associated with sporadic AVM formation, which are located in genes responsible for angiogenesis [7–11]. However, there is a surprising lack of modern literature focusing on possible structural embryologic explanations of AVM formation during arterial and venous development. AVMs are likely lesions with multifactorial origins, consisting of physiological, genetic, mechanical, and embryological mechanisms. In normal arteriovenous differentiation, ephrin B2 (EphB2) is an early arterial marker, whereas ephrin B4 (EphB4) denotes venous identity even before the onset of circulation. There is also a varying degree of endothelial plasticity that is largely a result of hemodynamic forces that influence genetic expression of these markers involved in arteriovenous differentiation [12]. While it is proven that these expression patterns regulate vessel differentiation before the onset of circulation in the developing axial trunk, it has recently been shown that the cranial vasculature may not in fact undergo arteriovenous differentiation until after the presence of blood flow and development might instead occur similarly to other areas where arteries hierarchically give rise to veins [13,14]. Thus, it is possible that aberrant embryological cranial blood flow in undeveloped endothelial tubes may give rise to defects in arteriovenous differentiation, potentially causing vascular pathologies such as AVMs. Considering this and other recent studies examining normal vascular development, we discuss a hierarchical embryological mechanism for the pathogenesis of AVMs.

2. Hierarchical vessel development While most researchers concede that genetic factors predominantly affect the formation and differentiation of blood vessels in the axial embryo, many propose that hemodynamic forces provide a great degree of plasticity in the development of arteries versus veins. In fact, in some anatomic regions like the developing axial embryo and yolk sac, it has been demonstrated that higher-flow arteries give rise to lower-flow veins [14,15]. Beginning with the onset of perfusion, the basic vascular framework becomes remodeled as morphologically distinct arteries and veins develop beyond immature primary plexuses. While investigating this process of flow-regulating vascular differentiation, Le Noble et al. proposed a novel mechanism in the differentiation of arteries and veins [14]. Using the vitelline artery and vein from a chick embryo as a model, small capillary-like vessels, which are part of the vascular plexus, are seen branching from the developing artery and eventually disconnect. These small blind-ending vessels then specifically project to the venular plexus, fuse, and contribute to the newly formed secondary venous vessel, thus restoring their flow. A very similar process occurs early on more centrally in the axial embryo, where the cardinal vein develops from ventral migration of angioblasts derived from the primitive dorsal aorta [15]. Many different factors contribute to the migration of these angioblasts and eventual formation of the cardinal vein, but Herbert et al. elegantly demonstrated that vascular endothelial growth factor (VEGF) limits ventral sprouting whereas reduced EphB2 expression promotes excessive ventral migration and formation of a single fused vessel [15]. In this hierarchical series of events, primitive arterial vessels donate smaller caliber vessels to the immature venous plexus, which consequently remodel to form early veins; this process is seen as arteries giving rise to veins. Much previous work has been devoted to identifying factors necessary for arteriovenous differentiation, but this study by Herbert et al. [15] is the first to depict exactly how these signaling molecules act to form vein from artery. The process depicted in this model has now been observed both

127

centrally, before the onset of circulation with formation of the cardinal vein, and peripherally, after circulation in the embryonic yolk sac. In early stages of embryonic tissue development, arterial growth is favored in the proximal to distal direction, as the distal highdensity capillary beds initially provide a path of least resistance [16]. Thus, a loop-like structure where the artery and vein run in series with one another is initially favored when the width of the developing tissue is greater than its length. As the tissue elongates, the resistance of this route increases, and capillary sprouts from the growing artery disconnect, as described previously, exhibiting positive feedback for a new vessel configuration in which veins form parallel to existing arteries and provide a new path of least resistance. This is a newly described process in which arterial flow exerts morphological control over venous patterning and development. Although flow-driven studies are specifically examining the developing vasculature of the embryonic yolk sac, it is thought that the cranial vasculature may also develop subsequent to the onset of circulation and, therefore, could be governed by similar mechanisms. Classically, EphB2 and EphB4 are two markers for arterial and venous identity, but kdrl and etsrp expression are other ways of designating arteries and veins, respectively [17]. Proulx et al. are the first to point out that within endothelial cells of the developing cranial vasculature, just before the onset of circulation, there is relatively equal expression of these two genes; this indicates that differentiation likely occurs after blood flow [13]. As a result, blood flow may be a key factor in the distinction of intracranial arteries and veins, where high-flow proximal vessels (arteries) give rise to low-flow distal vessels (veins). This is separate from the rest of the body where it has been clearly shown that EphB2 and EphB4, downstream of shh/vegf expression, delineate an arterial or venous fate well before the commencement of circulation [18]. With these two different processes in mind, it is possible that the cranial vasculature represents a discrete entity of vasculogenesis and angiogenesis within the embryo. Circulation likely has a greater influence on the differentiation of arteries and veins intracranially, which could potentially be a source of pathology in cases of failed differentiation and may explain the commonality of AVMs in the central nervous system relative to other locations.

3. Failed hierarchical arteriovenous differentiation as an embryologic source of AVM formation In a hierarchical series of events where relatively high-flow arteries give rise to veins, it is conceivable that several vascular pathologies may arise from mechanical defects, genetic defects, or some combination of the two. Just as in the early stages of embryonic yolk sac vasculogenesis and angiogenesis, we propose that in normal development, endothelial angioblasts coalesce to form an initial primary capillary plexus, which subsequently undergoes remodeling upon perfusion to produce early arteries [14]. As these arteries are perfused, their capillary sprouts disconnect, resulting in dangling capillary sprouts that lack circulation. These blind-ending “blood-filled spots” then undergo remodeling and fuse to produce a newly formed venous vessel. Because of the arteriovenous shunt observed in AVMs, it is possible that a defect in this capillary sprout detachment may result in lingering connections to the parent artery and an abnormal fistula between the developing artery and vein, leading to development of an AVM. Due to the lack of an adequate capillary bed and aberrant hemodynamics between the arterial and venous channels, genetic markers that normally delineate artery versus vein persist within the AV shunt but the channels lack the ability to undergo appropriate remodeling. This initial structural developmental defect may be essential in the formation of cerebral AVMs, and genetic predispositions, discussed in detail in the

128

W.L. Ramey et al. / Clinical Neurology and Neurosurgery 126 (2014) 126–129

Fig. 1. The hierarchical model of vascular formation. Experimental data suggests that arteries and veins sprout from a common precursor (A). Similarly lymphatics arise from venous precursors. Although the identity of signaling factors allowing this sprouting differentiation is not well established, the identity of the molecules involved are likely to be the same in arteriovenous (B) and venolymphatic (C) differentiation. Used with permission from Barrow Neurological Institute.

next section, may act as a “second hit,” allowing growth and maturation of AVMs. Additionally, several proteins that are exclusively expressed in endothelium of the developing fetal brain are found in adult AVM tissue—a fact that supports the idea of embryologic derivation of AVMs and indicates this “first hit” likely occurs during fetal vascular development [19]. The notion of low-flow tissues originating from higher-flow tissues is not unfamiliar, for it is known that veins subsequently give rise to the lymphatic vessels [20–22]. Not surprisingly, abnormal expression of several genes, such as VEGFR2 and VEGFR3, involved in lymphoid endothelial cell migration from precursor veins has been implicated in several rare lymphatic pathologies like lymphangiomas and some lymphangiodysplasias [23]. A protein required for the proper partitioning of intestinal lymphatic vasculature from venous vessels inherently supports the proposed mechanism for the embryogenesis of AVMs. Angiopoietin-like protein 4 (ANGPTL4) is a glycosylated protein produced by enterocytes that mediates lymphangiogenesis and is essential to the separation of venous and lymphatic circulation [24]. It also has pro- and anti-angiogenic effects involved in the constant vascular remodeling of AVMs, indicating why polymorphisms in the ANGPTL4 gene may be a risk factor for development of cerebral AVMs [25]. Because it is associated with susceptibility to brain AVM formation and clearly aids in the separation of venous and lymph vessels, it is conceivable that this protein is used repeatedly during the formation of veins from arteries and of lymphatics from veins (Fig. 1). Although encountered frequently in neurosurgery, both AVMs and head and neck lymphatic malformations are considered rare, with clinical incidences of substantially less than 1 percent [26,27]. In line with this model of hierarchical vascular differentiation, it is not surprising that there are no reported cases of developmental arteriolymphatic malformations. Given the flow-related development of blood vessels and the hierarchical nature in which these malformations arise, embryologic formation of a congenital arteriolymphatic shunt does not seem feasible.

4. The Effect of SNPs on the embryogenesis of AVMs Due to the rarity with which familial AVMs are reported in the literature, it has up until recently been commonplace to suggest that genetics do not play a significant role in the pathogenesis of cerebral AVMs that are not associated with diseases like hereditary hemorrhagic telangiectasia. However, a modern wave of literature investigating genetic factors suggests that polymorphisms seen in a diverse set of genes may be at least partially responsible for development of sporadic AVMs. Because angiogenic and inflammatory factors have been implicated in AVM growth and physiology, it is not surprising that SNPs in these genes are associated with AVM formation [7–11,28–30]. In a recent joint analysis limited to SNPs investigated in more than one study, Sturiale et al. found one SNP located in the activin-like kinase 1 (ALK1) gene that was significantly associated with AVM susceptibility [31]. ALK1 is a gene essential for development of distinct arterial and venous vascular beds, as well as several other processes involved in vascular remodeling and endothelial cell differentiation; this supports the notion of an embryologic source for AVM formation. We propose that the ALK1 SNP and other yet undiscovered polymorphisms are necessary components in the embryogenesis of AVMs. After developmental structural anomalies formed via the previously described embryological vascular dysgenesis, it is feasible that SNPs act as a “second hit” in the development of sporadic cerebral AVMs. It has been proposed that due to the focal nature of vascular malformations, a second hit, either environmental or genetic, affects a single localized area rather than the vasculature as a whole [32–35]. Although these previously investigated second hits are postulated to occur after somatic mutations with coexisting germline mutations, a similar mechanism may be at work in the presence of an embryologic structural abnormality. Thus, we propose that both an environmental hit (hierarchical embryological structural abnormality) and a genetic hit (SNP) act in concert to form a focal cerebral AVM.

W.L. Ramey et al. / Clinical Neurology and Neurosurgery 126 (2014) 126–129

5. Conclusions Recent experimental data suggests that defects in the flowrelated differentiation of vasculature gives rise to vascular malformations. Additionally, considering that AVMs are likely multifactorial in origin, SNPs affecting genes in inflammatory or angiogenic pathways may act as a “second hit” when present in the setting of a structural embryologic anomaly. An improved understanding of the biology of AVM formation may result in novel nonsurgical therapies for this class of diseases. Conflict of interest The authors have no personal financial or institutional interest in any of the materials or devices described in this article. References [1] Kappel A, Ronicke V, Damert A, Flamme I, Risau W, Breier G. Identification of vascular endothelial growth factor (VEGF) receptor-2 (Flk-1) promoter/enhancer sequences sufficient for angioblast and endothelial cellspecific transcription in transgenic mice. Blood 1999;93:4284–92. [2] Moftakhar P, Hauptman JS, Malkasian D, Martin NA. Cerebral arteriovenous malformations, Part 1: Cellular and molecular biology. Neurosurg Focus 2009;26:E10. [3] Moftakhar P, Hauptman JS, Malkasian D, Martin NA. Cerebral arteriovenous malformations, Part 2: Physiology. Neurosurg Focus 2009;26:E11. [4] Lasjaunias P. A revised concept of the congenital nature of cerebral arteriovenous malformations. Interv Neuroradiol: J Perither Neuroradiol Surg Proced Relat Neurosci 1997;3:275–81. [5] Mullan S, Mojtahedi S, Johnson DL, Macdonald RL. Embryological basis of some aspects of cerebral vascular fistulas and malformations. J Neurosurg 1996;85:1–8. [6] Teddy P, Valavanis A, Duvernoy HM, Yas¸argil MG. AVM of the brain, history, embryology, pathological considerations, hemodynamics, diagnostic studies, microsurgical anatomy, vol. 1. Thieme; 1987. [7] Sturiale CL, Gatto I, Puca A, D’Arrigo S, Giarretta I, Albanese A, et al. Association between the rs1333040 polymorphism on the chromosomal 9p21 locus and sporadic brain arteriovenous malformations. J Neurol Neurosurg Psychiatry 2013;84:1059–62. [8] Pawlikowska L, Tran MN, Achrol AS, Ha C, Burchard E, Choudhry S, et al. Polymorphisms in transforming growth factor-beta-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations. Stroke J Cereb Circ 2005;36:2278–80. [9] Mikhak B, Weinsheimer S, Pawlikowska L, Poon A, Kwok PY, Lawton MT, et al. Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations. Cerebrovasc Dis (Basel, Switz) 2011;31:338–45. [10] Simon M, Franke D, Ludwig M, Aliashkevich AF, Koster G, Oldenburg J, et al. Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system. J Neurosurg 2006;104:945–9. [11] Chen H, Gu Y, Wu W, Chen D, Li P, Fan W, et al. Polymorphisms of the vascular endothelial growth factor A gene and susceptibility to sporadic brain arteriovenous malformation in a Chinese population. J Clin Neurosci: Off J Neurosurg Soc Australas 2011;18:549–53. [12] Moyon D, Pardanaud L, Yuan L, Breant C, Eichmann A. Plasticity of endothelial cells during arterial–venous differentiation in the avian embryo. Development (Camb, Engl) 2001;128:3359–70. [13] Proulx K, Lu A, Sumanas S. Cranial vasculature in zebrafish forms by angioblast cluster-derived angiogenesis. Dev Biol 2010;348:34–46. [14] le Noble F, Moyon D, Pardanaud L, Yuan L, Djonov V, Matthijsen R, et al. Flow regulates arterial–venous differentiation in the chick embryo yolk sac. Development (Camb, Engl) 2004;131:361–75.

129

[15] Herbert SP, Huisken J, Kim TN, Feldman ME, Houseman BT, Wang RA, et al. Arterial–venous segregation by selective cell sprouting: an alternative mode of blood vessel formation. Science (New York, NY) 2009;326:294–8. [16] Al-Kilani A, Lorthois S, Nguyen TH, Le Noble F, Cornelissen A, Unbekandt M, et al. During vertebrate development, arteries exert a morphological control over the venous pattern through physical factors. Phys Rev E Stat Nonlin Soft Matter Phys 2008;77:051912. [17] Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, et al. Notch signaling is required for arterial–venous differentiation during embryonic vascular development. Development (Camb, Engl) 2001;128:3675–83. [18] Lawson ND, Vogel AM, Weinstein BM. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 2002;3:127–36. [19] Koizumi T, Shiraishi T, Hagihara N, Tabuchi K, Hayashi T, Kawano T. Expression of vascular endothelial growth factors and their receptors in and around intracranial arteriovenous malformations. Neurosurgery 2002;50:117–24, discussion 124-116. [20] Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, et al. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev 2007;21:2422–32. [21] Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 1995;92:3566–70. [22] Jain RK. Molecular regulation of vessel maturation. Nat Med 2003;9:685–93. [23] Wilting J, Buttler K, Rossler J, Norgall S, Schweigerer L, Weich HA, et al. Embryonic development and malformation of lymphatic vessels. Novartis Found Symp 2007;283:220–7, discussion 227–229, 238–241. [24] Bäckhed F, Crawford PA, O’Donnell D, Gordon JI. Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor. Proc Natl Acad Sci 2007;104:606–11. [25] Mikhak B, Weinsheimer S, Pawlikowska L, Poon A, Kwok P-Y, Lawton MT, et al. Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations. Cerebrovasc Dis 2011;31:338–45. [26] Berman MF, Sciacca RR, Pile-Spellman J, Stapf C, Connolly Jr ES, Mohr JP, et al. The epidemiology of brain arteriovenous malformations. Neurosurgery 2000;47:389–96, discussion 397. [27] Filston HC. Hemangiomas, cystic hygromas, and teratomas of the head and neck. Semin Pediatr Surg 1994;3:147–59. [28] Kim H, Hysi PG, Pawlikowska L, Choudhry S, Gonzalez Burchard E, Kwok PY, et al. Population stratification in a case–control study of brain arteriovenous malformation in Latinos. Neuroepidemiology 2008;31:224–8. [29] Kim H, Hysi PG, Pawlikowska L, Poon A, Burchard EG, Zaroff JG, et al. Common variants in interleukin-1-Beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation. Cerebrovasc Dis (Basel, Switz) 2009;27:176–82. [30] Fontanella M, Rubino E, Crobeddu E, Gallone S, Gentile S, Garbossa D, et al. Brain arteriovenous malformations are associated with interleukin-1 cluster gene polymorphisms. Neurosurgery 2012;70:12–7. [31] Sturiale CL, Puca A, Sebastiani P, Gatto I, Albanese A, Di Rocco C, et al. Single nucleotide polymorphisms associated with sporadic brain arteriovenous malformations: where do we stand? Brain J Neurol 2013;136: 665–81. [32] Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet 2009;18:919–30. [33] Gault J, Awad IA, Recksiek P, Shenkar R, Breeze R, Handler M, et al. Cerebral cavernous malformations: somatic mutations in vascular endothelial cells. Neurosurgery 2009;65:138–44, discussion 144-135. [34] Xu B, Wu YQ, Huey M, Arthur HM, Marchuk DA, Hashimoto T, et al. Vascular endothelial growth factor induces abnormal microvasculature in the endoglin heterozygous mouse brain. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 2004;24:237–44. [35] Hao Q, Su H, Marchuk DA, Rola R, Wang Y, Liu W, et al. Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation. Am J Physiol Heart Circ Physiol 2008;295:H2250–6.

A hierarchical model for the development of cerebral arteriovenous malformations.

Cerebral arteriovenous malformations (AVMs) are vascular lesions whose pathogenesis, although not fully elucidated, is likely multifactorial. Recent r...
380KB Sizes 5 Downloads 7 Views