Preclinical extracranial aneurysm models for the study and treatment of brain aneurysms: A systematic review.

Animal models make an important contribution to our basic understanding of the pathobiology of human brain aneurysms, are indispensable in testing novel treatment approaches, and are essential for training interventional neuroradiologists and neurosurgeons. Researchers are confronted with a broad diversity of models and techniques in various species. This systematic review aims to summarize and categorize extracranial aneurysm models and their characteristics, discuss advantages and disadvantages, and suggest the best use of each model. We searched the electronical Medline/PubMed database between 1950 and 2020 to identify main models and their refinements and technical modifications for creation of extracranial aneurysms. Each study included was assessed for aneurysm-specific characteristics, technical details of aneurysm creation, and histological findings. Among more than 4000 titles and abstracts screened, 473 studies underwent full-text analysis. From those, 68 different techniques/models in five different species were identified, analyzed in detail, and then grouped into one of the five main groups of experimental models as sidewall, terminal, stump, bifurcation, or complex aneurysm models. This systematic review provides a compact guide for investigators in selecting the most appropriate model from a range of techniques to best suit their experimental goals, practical considerations, and laboratory environment

Aivovaltimoaneurysman seinämän patobiologia

Backround and Purpose The often fatal (in 50-35%) subarachnoid hemorrhage (SAH) caused by saccular cerebral artery aneurysm (SCAA) rupture affects mainly the working aged population. The incidence of SAH is 10-11 / 100 000 in Western countries and twice as high in Finland and Japan. The estimated prevalence of SCAAs is around 2%. Many of those never rupture. Currently there are, however, no diagnostic methods to identify rupture-prone SCAAs from quiescent, (dormant) ones. Finding diagnostic markers for rupture-prone SCAAs is of primary importance since a SCAA rupture has such a sinister outcome, and all current treatment modalities are associated with morbidity and mortality. Also the therapies that prevent SCAA rupture need to be developed to as minimally invasive as possible. Although the clinical risk factors for SCAA rupture have been extensively studied and documented in large patient series, the cellular and molecular mechanisms how these risk factors lead to SCAA wall rupture remain incompletely known. Elucidation of the molecular and cellular pathobiology of the SCAA wall is needed in order to develop i) novel diagnostic tools that could identify rupture-prone SCAAs or patients at risk of SAH, and to ii) develop novel biological therapies that prevent SCAA wall rupture. Materials and Methods In this study, histological samples from unruptured and ruptured SCAAs and plasma samples from SCAA carriers were compared in order to identify structural changes, cell populations, growth factor receptors, or other molecular markers that would associate with SCAA wall rupture. In addition, experimental saccular aneurysm models and experimental models of mechanical vascular injury were used to study the cellular mechanisms of scar formation in the arterial wall, and the adaptation of the arterial wall to increased mechanical stress. Results and Interpretation Inflammation and degeneration of the SCAA wall, namely loss of mural cells and degradation of the wall matrix, were found to associate with rupture. Unruptured SCAA walls had structural resemblance with pads of myointimal hyperplasia or so called neointima that characterizes early atherosclerotic lesions, and is the repair and adaptation mechanism of the arterial wall after injury or increased mechanical stress. As in pads of myointimal hyperplasia elsewhere in the vasculature, oxidated LDL was found in the SCAA walls. Immunity against OxLDL was demonstrated in SAH patients with detection of circulating anti-oxidized LDL antibodies, which were significantly associated with the risk of rupture in patients with solitary SCAAs. Growth factor receptors associated with arterial wall remodeling and angiogenesis were more expressed in ruptured SCAA walls. In experimental saccular aneurysm models, capillary growth, arterial wall remodeling and neointima formation were found. The neointimal cells were shown to originate from the experimental aneurysm wall with minor contribution from the adjacent artery, and a negligible contribution of bone marrow-derived neointimal cells. Since loss of mural cells characterizes ruptured human SCAAs and likely impairs the adaptation and repair mechanism of ruptured or rupture-prone SCAAs, we investigated also the hypothesis that bone marrow-derived or circulating neointimal precursor cells could be used to enhance neointima formation and compensate the impaired repair capacity in ruptured SCAA walls. However, significant contribution of bone marrow cells or circulating mononuclear cells to neointima formation was not found.Aivovaltimoaneurysma (AA), ja sen puhkeamisen aiheuttama hengenvaarallinen lukinkalvonalainen verenvuoto (SAV), on suomalaisessa väestössä poikkeuksellisen yleinen sairaus. Suomessa on vuosittain noin 1000 uutta SAV potilasta, joista lähes puolet menehtyy. AA:n kantajia arvioidaan olevan huomattavasti enemmän, arviolta noin 2% väestöstä. Toistaiseksi ei tiedetä miksi osa AA:ista puhkeaa kun suuri osa säilyy puhkeamattomina läpi kantajiensa elämän. Vaikka AA:n ja SAV:n riskitekijät (tärkeimpinä tupakointi ja korkea verenpaine) ovat hyvin tiedossa, AA:n seinämän biologia ja sen puhkeamiseen johtavat prosessit ovat puutteellisesti tunnettuja. AA:n seinämän puhkeamiseen johtavien solutason tapahtumien selvittäminen on ensiarvoisen tärkeää i) jotta voitaisiin kehittää uusia diagnostisia menetelmiä joiden avulla voidaan erottaa vuotoriskissä olevat AA:t niistä jotka eivät koskaan vuoda, sekä ii) jotta voitaisiin kehittää AA:n seinämän puhkeamisen ehkäiseviä lääkehoitoja tai muita vähän invasiivisia biologisia hoitoja. Nykyisin AA:n seinämän puhkeaminen voidaan ehkäistä kallonsisäisellä mikrokirurgisella ligaatiolla tai tukkimalla AA suonensisäisesti katetrin kautta viedyillä metallikierukoilla. Molempiin hoitoihin liittyy vammautumisen riski, ja lisäksi etenkin suonensisäisesti hoidetut AA:t saattavat uusiutua. Tämän tutkimuksen tarkoituksena oli selvittää vuotaneiden ja vuotamattomien AA:n seinämien rakenteellisia eroja, sekä tutkia niihin liittyviä biologisia mekanismeja. Lisäksi tutkittiin kokeellisessa aneurysmamallissa aneurysman seinämän rakenteellisia muutoksia sekä niihin osallistuvien solujen alkuperää. Tutkimuksessa todettiin, että vuotamattomien AA:n seinämä on useimmiten tukikudokseltaan ehyempi ja solurikkaampi kuin puhjenneen AA:n seinämä ja että puhjenneen AA:n seinämässä on enemmän tulehdussoluja kuin vuotamattoman AA:n seinämässä. Vuotamattoman AA:n seinämä todettiin muistuttavan rakenteeltaan korkean verenpaineen, mekaanisen stressin, ja valtimokovettumataudin valtimoihin aiheuttamia muutoksia. Tutkimuksessa todettiinkin, että samoin kuin edellä mainituissa valtimon seinämän muutoksissa, myös AA:n seinämään kertyy LDL-kolesteroli partikkeleita, jotka hapettuvat ja muunnuttuaan saattavat käynnistää AA:n seinämässä tulehdusreaktion. Potilailla, joilla AA oli puhjennut, todettiin verenkierrossa useammin ja enemmän vasta-aineita hapettunutta LDL-kolesterolia vastaan kuin vuotamattoman AA:n kantajilla. Lisäksi kartoitettiin AA:n seinämän soluja sääteleviä kasvutekijäreseptoreita, joista ainoastaan IGF-kasvutekijän reseptori 1 löytyi lähes kaikkien AA:ien seinämistä ja lähes kaikista AA:n seinämän soluista. Reseptoreista VEGF-kasvutekijän reseptori 1 näytti assosioituvan AA:n seinämän puhkeamiseen. Näiden kasvutekijäreseptoreiden toiminnan tarkempi selvittäminen AA:n seinämässä vaikuttaa AA:n seinämään vaikuttavan lääkehoidon kannalta lupaavalta kohteelta, joskin lisätutkimuksia ja vahvistavia tuloksia tarvitaan. Kokeellisessa aneurysmamallissa tutkittiin seinämän uudelleen muovautumiseen ja arpeutumiseen osallistuvien solujen alkuperää. Mallissa todettiin rakenteellisia muutoksia, jotka muistuttivat vuotamattoman AA:n seinämää. Kokeellisessa mallissa seinämän uudelleen muovautumiseen osallistuneet solut olivat peräisin lähes täysin aneurysman seinämästä. Koska ihmisen puhjenneen AA:n seinämä on usein hyvin vähäsoluinen, vaikuttaa kokeellisessa mallissa tehtyjen havaintojen perusteella, että puhjennen AA:n seinämän arpeutumis- ja paranemiskyky on vuotamattomaan AA:aan nähden vajavainen. Muualta kehosta peräisin olevilla sidekudossoluilla saatettaisiin voida kompensoida puhjenneen AA:n heikkoa seinämää ja arpeutumista. Tässä tutkimuksessa todettiin luuydinperäisten sidekudossolujen osuuden kokeellisen AA:n seinämän arpeutumiseen olevan erittäin niukkaa. Lisäksi tutkittiin ihmisen verenkierrosta eristettyjen solujen käyttöä mekaanisesti vaurioitetun valtimon seinämän arpeutumisen lisäämisessä. Ihmisen verenkierrosta peräisin olevin stimuloimattomien solujen ei kuitenkaan havaittu osallistuvan valtimon seinämän vaurion paranemiseen

Aivovaltimoaneurysmat ja suun terveys

publishedVersionPeer reviewe

Intraluminal cell transplantation prevents growth and rupture in a model of rupture-prone saccular aneurysms.

BACKGROUND AND PURPOSE Aneurysm occlusion by intraluminal thrombus formation is the desired effect of all endovascular treatments. Intraluminal thrombus may, however, recanalize and be absorbed, unless it is infiltrated by cells that turn it into fibrous tissue (neointima). Because ruptured aneurysm walls are characterized by loss of smooth muscle cells, we assessed the impact of mural cell loss on wall remodeling of thrombosed aneurysms and investigated whether neointima formation could be enhanced by direct transplantation of cells into the thrombus. METHODS Sidewall aneurysms were microsurgically created in rats (n=81). Certain aneurysms were decellularized. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil-labeled smooth muscle cells were injected into 25 of 46 fibrin embolized aneurysms. Recanalization and aneurysm growth were monitored with magnetic resonance angiography. Endoscopy, optical projection tomography, histology, and immunohistochemistry were used to study the fate of transplanted cells, thrombus organization, and neointima formation. RESULTS Decellularized embolized aneurysms demonstrated higher angiographic recurrence compared with decellularized embolized aneurysms with transplanted cells (P=0.037). Local cell replacement at the time of thrombosis resulted in better histological neointima formation than both nondecellularized embolized aneurysms (P<0.001) and decellularized embolized aneurysms (P=0.002). Aneurysm growth and rupture were observed exclusively in decellularized embolized aneurysms. CONCLUSIONS Lack of smooth muscle cells in the aneurysm wall promotes wall degradation, aneurysm growth and rupture, even if the aneurysm is occluded by luminal thrombus. Transplantation of smooth muscle cells into the luminal thrombus can reduce this degenerative remodeling

Intraluminal Cell Transplantation Prevents Growth and Rupture in a Model of Rupture-Prone Saccular Aneurysms

BACKGROUND AND PURPOSE Aneurysm occlusion by intraluminal thrombus formation is the desired effect of all endovascular treatments. Intraluminal thrombus may, however, recanalize and be absorbed, unless it is infiltrated by cells that turn it into fibrous tissue (neointima). Because ruptured aneurysm walls are characterized by loss of smooth muscle cells, we assessed the impact of mural cell loss on wall remodeling of thrombosed aneurysms and investigated whether neointima formation could be enhanced by direct transplantation of cells into the thrombus. METHODS Sidewall aneurysms were microsurgically created in rats (n=81). Certain aneurysms were decellularized. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil-labeled smooth muscle cells were injected into 25 of 46 fibrin embolized aneurysms. Recanalization and aneurysm growth were monitored with magnetic resonance angiography. Endoscopy, optical projection tomography, histology, and immunohistochemistry were used to study the fate of transplanted cells, thrombus organization, and neointima formation. RESULTS Decellularized embolized aneurysms demonstrated higher angiographic recurrence compared with decellularized embolized aneurysms with transplanted cells (P=0.037). Local cell replacement at the time of thrombosis resulted in better histological neointima formation than both nondecellularized embolized aneurysms (P<0.001) and decellularized embolized aneurysms (P=0.002). Aneurysm growth and rupture were observed exclusively in decellularized embolized aneurysms. CONCLUSIONS Lack of smooth muscle cells in the aneurysm wall promotes wall degradation, aneurysm growth and rupture, even if the aneurysm is occluded by luminal thrombus. Transplantation of smooth muscle cells into the luminal thrombus can reduce this degenerative remodeling