Экспрессия интегринов и пролиферативное поведение гладкомышечных клеток в онтогенезе аорты крысы тема диссертации и автореферата по ВАК РФ 03.00.04, кандидат биологических наук Матвеева, Наталия Алексеевна

• Матвеева, Наталия Алексеевна
• кандидат биологических наук
• 2008

Оглавление диссертации кандидат биологических наук Матвеева, Наталия Алексеевна

СПИСОК СОКРАЩЕНИЙ.

ВВЕДЕНИЕ.

1. ОБЗОР ЛИТЕРАТУРЫ.

1.1. Морфогенез сосудов.

1.1.1. Развитие сосудистой стенки.

1.1.2. Маркеры дифференцировки ГМК.

1.1.3. Роль гемодинамических факторов в развитии сосудистой стенки.

1.1.4. Экстрацеллюлярный матрикс в развитии сосуда.

1.1.5. Миграция клеток сосудистой стенки.

1.1.6. Пролиферация ГМК.

1.1.7. Регуляция пролиферации и дифференцировки клеток сосудистой стенки.

1.1.8. Гетерогенность ГМК.

1.2. Интегрины в морфогенезе сосудов.

1.2.1. Строение и разнообразие интегриновых рецепторов.

1.2.2. Модуляция аффинности и специфичности интегринов. Интегрин-опосредованная передача сигнала.

1.2.3. Взаимодействие интегринов с лигандами.

1.2.4. Интегрины в эмбриогенезе.

1.2.5. Интегрины и поведение клеток.

2. МАТЕРИАЛЫ И МЕТОДЫ.

2.1 Использованные реактивы.

2.2 Получение эмбрионов крысы.

2.3 Изучение экспрессии интегринов и белков внеклеточного матрикса. Иммуноцитохимия.

2.4 Изучение пролиферативного поведения гладкомышечных клеток. Авторадиография.

2.5 Статистическая обработка результатов.

3. результаты и обсуждение.

3.1. Пролиферативное поведение гладкомышечных клеток в онтогенезе аорты крысы.

3.1.1. Первая возрастная группа (6-21 день после рождения).

3.1.2. Вторая возрастная группа (26 - 101 день после рождения).

3.1.3. Третья возрастная группа (52 - 127 день после рождения).

3.2 Изучение экспрессии интегринов и белков внеклеточного матрикса.

Введение диссертации (часть автореферата) на тему «Экспрессия интегринов и пролиферативное поведение гладкомышечных клеток в онтогенезе аорты крысы»

Механизм регуляции поведения клеток во многом неясен. На сегодняшний день мы знаем пока лишь часть этапов этого процесса, включающего регулирование экспрессии групп генов, воздействие факторов роста и других биологически активных молекул, взаимодействие клеток друг с другом и с экстрацеллюлярным матриксом (ЭЦМ) и т.п. Одним из важнейших звеньев в цепи регулирования поведения является интегрин-опосредованное взаимодействие клетки с матриксом, которое во многом определяет ее судьбу. Имеются многочисленные данные, указывающие, что различные компоненты ЭЦМ способны влиять на миграцию, пролиферацию, дифференцировку и апоптоз клеток, обеспечивая взаимосвязь цитоскелета и ЭЦМ (Montesano et al., 1983; Pratt et al., 1984; Schwartz, 1984; Choquet et al., 1997; Jones et al., 1997; Pepper, 1997; Heerkens et al., 2007; Hynes, 2007, Stupack, 2007; Takada et al., 2007). Кроме того, как стало ясно в последнее время (Larsen et al., 2006), часть интегринов играет огромную роль в ремоделировании матрикса не только в эмбриональном развитии, но и в постнатальном периоде, выступая в роли важнейшего участника репаративных процессов в тканях богатых ЭЦМ.

Морфогенез сосудистой системы включает миграцию, пролиферацию и дифференцировку предшественников гладкомышечных клеток (ГМК). Причем, ГМК, которые составляют основную массу клеток сосудистой стенки артерий и вен характеризуются целым рядом особенностей дифференцировки. Прежде всего, это два фенотипа: эмбриональный или синтетический и взрослый или сократительный. ГМК присуще сочетание активной пролиферации в эмбриональном и раннем постнатальном периоде с продукцией большого числа матриксных белков и формированием базальной мембраны. Митотическая активность ГМК затухает постепенно, и клетки выходят в состояние покоя, но продолжают синтезировать внеклеточный матрикс.

Надо отметить, что ГМК, пожалуй, единственный тип клеток у птиц и млекопитающих, которые способны в ответ на внешние стимулы выходить из покоя, что сопровождается модификацией их фенотипа из сократительного в синтетический (т.е. наблюдается процесс эмбрионализации гладкомышечной ткани). Это имеет огромное значение при развитии атеросклеротического поражения сосудов. R. Ross выдвинул концепцию развития атеросклероза, согласно которой повреждение сосуда вызывает миграцию ГМК медии и формировании ими неоинтимы (Ross, Glomset, 1976). Однако в последнее время было показано, что в формирование неоинтимы и атеросклеротической бляшки вносят свой вклад и клетки-предшественники ГМК, которые мигрируют в зону поражения по системе vasa vasorum из адвентиции и из периферической крови (Margariti et al., 2006). Кроме того, следует учитывать, что в ходе эмбрионального развития ГМК в различных сосудах происходят из разных источников (Hirschi, Majesky, 2004; Margariti et al., 2006). Также на сегодняшний день накоплен огромный материал, свидетельствующий, что популяция ГМК крупных артериальных сосудов и в частности аорты гетерогенна по целому ряду признаков.

Перечисленные выше особенности дифференцировки ГМК сосудов свидетельствуют, что огромную роль в поведении этих клеток играет взаимодействие с матриксом. Интегрины как рецепторы для компонентов матрикса в полной мере отражают свое название и являются важнейшими участниками морфогенеза сосудистой системы, как в эмбриональном, так и в постнатальном периоде (п/н). Поэтому представляется актуальным изучение экспрессии различных интегринов в онтогенезе аорты крысы и взаимосвязи их экспрессии и пролиферативного поведения ГМК.

Цель работы - оценка репертуара экспрессированных на поверхности гладкомышечных клеток интегринов (31- и (33- семейств, как важнейших рецепторов к компонентам внеклеточного матрикса, и сопоставление полученных результатов с особенностями пролиферативного поведения гладкомышечных клеток в ходе эмбрионального и постнатального развития аорты крысы.

Для достижения цели были поставлены следующие задачи:

1. Методом «отложенной метки» с использованием тимидина, меченого тритием, исследовать особенности пролиферативного поведения гладкомышечных клеток в морфогенезе аорты крысы с раннего постнатального периода и до наступления половой зрелости (с 6-го дня до 4-х месяцев после рождения).

2. Методом иммуноцитохимии исследовать экспрессию интегринов Р1- и РЗ-семейств на гладкомышечных клетках в онтогенезе аорты крысы в эмбриональном и постнатальном периодах.

3. Методом иммуноцитохимии исследовать экспрессию основных компонентов матрикса в онтогенезе аорты крысы в эмбриональном и постнатальном периодах.

4. Сопоставить картину экспрессии интегринов на поверхности гладкомышечных клеток с пролиферативным поведением г ладкомышечных клеток в ходе онтогенеза аорты крысы.

Заключение диссертации по теме «Биохимия», Матвеева, Наталия Алексеевна

выводы

1. Авторадиографическое исследование выявило гетерогенность по пролиферативному поведению популяции ГМК формирующейся аорты крысы. Выявлены две субпопуляции ГМК, отличающиеся по митотической активности: «быстрая» и «медленная».

2. Анализ экспрессии интегринов а1р1, а5р1, аурЗ и а2-, аб-субъединиц интегринов в ходе развития гладкомышечной ткани аорты крысы с 11-го дня в/у развития и до 4-х месяцев после рождения показал, что интегрины а1р1 (рецептор коллагена IV), а5р1 (фибронектиновый рецептор) и алфЗ (рецептор для фибриногена, витронектина, остеопонтина) экспрессируются на ГМК аорты крысы уже начиная с самых ранних этапов онтогенеза. Уровень их экспрессии постепенно повышается и сохраняется высоким в течение всей жизни животного.

3. а2-субъединица (рецептор коллагена I) и аб-убъединица (ламининовый рецептор) выявляются на достаточно высоком уровне только в конце эмбрионального периода и после рождения.

4. Не выявлено четкой смены экспрессии исследованных интегринов в зависимости от пролиферативного поведения ГМК развивающейся аорты крысы. Отсутствие четкой взаимосвязи между экспрессией исследованных интегринов и пролиферативным поведением ГМК в онтогенезе аорты крысы может объясняться особенностями дифференцировки ГМК, для которых характерно параллельное протекание процессов пролиферации и синтеза внеклеточного матрикса.

ЗАКЛЮЧЕНИЕ

Сосудистая система закладывается и начинает функционировать в онтогенезе очень рано. Основные процессы формирования стенки сосуда — миграция, пролиферация и дифференцировка ГМК. В настоящей работе нами предпринята попытка исследовать особенности пролиферативного поведения ГМК в морфогенезе аорты крысы. Проведенные нами исследования показали, что с возрастом в стенке аорты крысы пролиферация ГМК сильно снижается. Об этом свидетельствует падение ИМ с 23% на 6 сутки п/р до 2,5% на 26 и 52 сутки п/р. Наши данные о резком замедлении пролиферации ГМК согласуются с известными из литературы (Looker, Веггу, 1972; Yurukova et al., 1976). При анализе распределения ГМК по интенсивности мечения отчетливо выявляется гетерогенность по пролиферативному поведению популяции ГМК грудного отдела аорты крысы. На ранних этапах онтогенеза основная масса ГМК составляет «быстропролиферирующую» субпопуляцию, за счет которой происходит рост аорты. Другая субпопуляция — «медленная» - пролиферирует значительно медленнее и видимо пополняется клетками из первой субпопуляции.

Гетерогенность популяции ГМК взрослой ткани скорее всего объясняется различными сроками выхода клеток из клеточного цикла в состояние покоя в ходе эмбрионального и раннего п/н периода (Заварзин, 1967). Выход в состояние покоя клеток из «быстрой» субпопуляции на ранних сроках развития, вероятнее всего, происходит в Gl-периоде (Owens et al., 1983). А выход в состояние покоя клеток из «медленной» субпопуляции, скорее всего, происходит асинхронно на разных стадиях клеточного цикла (предположительно в Gl- и 02-периодах). Итак, можно сказать, что в аорте крысы существуют субпопуляции ГМК, различающиеся как по пролиферативной активности, так и по срокам выхода в покой, что отчетливо следует из наших результатов. Можно предположить, что и степень углубленности в покой и продвииутость по дифференцировке различных субпопуляций ГМК также может отличаться. Анализ литературных источников позволяет поставить вопрос о функциональной гетерогенности ГМК. Возможно, различные субпопуляции ГМК по-разному участвуют в функционировании сосуда в норме и в патологии (С1икЬоуа, Ко1еНап8ку, 1995). Надо отметить, что ГМК, находясь в состоянии покоя, способны в ответ на внешние стимулы (например, повреждение) выходить из покоя, и претерпевать модификацию фенотипа из сократительного в синтетический (т.е. эмбриональный). Можно предположить, что первыми отвечают на повреждение сосудистой стенки наименее углубленные в покой клетки. Скорее всего, это клетки, принадлежащие к «медленной» субпопуляции, длительное время сохраняющей способность вступать в клеточный цикл.

Характерной особенностью гладкомышечной ткани является крайне слабое клеточное обновление. Если ГМК в эмбриональном и раннем постнатальном периоде активно пролиферируют, то во взрослом сосуде обновление идет путем полиплоидизации. Полученные нами результаты свидетельствуют, что уже с момента рождения в ходе формирования стенки аорты из популяции исходных ГМК обособляется небольшой процент клеток, уходящих в состояние покоя. Итак, общая популяция ГМК аорты крысы состоит из нескольких субпопуляций. Большой интерес представляет изучение механизма возникновения и контроля гетерогенности как по срокам выхода, так и по углубленности в покой ГМК.

Другая особенность гладкомышечной ткани сосудистой стенки — мощное развитие ЭЦМ, который вырабатывают сами ГМК. Причем активная пролиферации и синтез матрикса в ГМК протекают параллельно. Участие ЭЦМ в формировании и функционировании как эмбриональных, так и взрослых сосудов, очевидно. Роль адгезивных рецепторов к компонентам матрикса на ГМК выполняют интегрины. Они участвуют в процессах адгезии и миграции клеток. Кроме того, в активированном состоянии интегрины участвуют в передаче сигнала в клетку. Сигнальная функция интегринов, прежде всего, связана с поддержанием целостности состава ЭЦМ и, следовательно, целостности ткани.

Из литературы известно, что интегрины способны как поддерживать пролиферацию, так и быть активными участниками ее ингибирования. Учитывая особенности дифференцировки ГМК аорты, мы постарались проследить экспрессию различных интегринов в онтогенезе аорты крысы и взаимосвязь их экспрессии и пролиферативного поведения ГМК. Мы исследовали экспрессию интегринов Р1- и Р3-семейств, которые являются рецепторами для основных компонентов ЭЦМ стенки аорты. Мы показали, что интегрины а1р1 (рецептор коллагена IV) и а5р1 (фибронектиновый рецептор) экспрессируются на ГМК аорты крысы уже начиная с самых ранних этапов онтогенеза. Уровень их экспрессии постепенно повышается и сохраняется высоким в течение всей жизни животного. а2 — субъединица (рецептор коллагена I) выявляется на достаточно высоком уровне только в конце беременности и после рождения. Несколько раньше выявляется аб субъединица (ламининовый рецептор). Со второй половины беременности постепенно увеличивается экспрессия аурз интегрина (рецептор для фибриногена, витронектина, остеопонтина). Хотя мы и провели исследование экспрессии основных белков ЭЦМ аорты, однако какой-либо периодичности их экспрессии выявлено не было. Возможно, это связано с использованием поликлональных антител, которые не позволяют отдифференцировать различные изоформы матриксных белков.

Изменения микроокружения является триггерным моментом в морфогенезе, так как смена состава матрикса приводит к изменению «соотношения» между дифференцировкой и пролиферацией клеток. В морфогенезе отдельных типов тканей ранее была описана периодическая смена репертуара интегринов. Так, по мере развития эпителия происходит изменение экспрессии интегринов и их локализации (Нейк & а1., 1991). Исследование развития сосудов в ЦНС у мышей показало, что в эмбриональном и раннем постнатальном периоде на эндотелиальных клетках преобладают a4pi и a5pi интегрины (фибронектиновые рецепторы). У взрослых на первый план выходят alpl и a6pl интегрины (ламининовые рецепторы). В соответствие с экспрессией интегриновых рецепторов происходит изменение в составе матрикса: количество фибронектина постепенно уменьшается, а ламинина -увеличивается (Milner, Campbell, 2002).

Проведенные исследования особенностей экспрессии в морфогенезе аорты человека aipi и a3pi интегринов и соответствующих им лигандов (Glukhova, Koteliansky 1995; Belkin et al., 1990) позволяет предположить, что взаимодействие alpl и a3pl интегринов с соответствующими компонентами базальной мембраны (например, с alp2yl ламинином, характерным для взрослых) вызывает созревание ГМК и поддерживает их в дифференцированном состоянии (Glukhova, Koteliansky 1995). Учитывая, что большинство компонентов ЭЦМ имеют многочисленные изоформы, по-разному экспрессированные в ходе развития, можно сказать, что взаимодействие одних и тех же интегриновых рецепторов с теми или иными вариантами матриксных белков может, как активировать, так и ингибировать пролиферацию и дифференцировку клеток.

Огромную роль в регуляции ангиогенеза играет интегрин avp3. Лигандами для него могут служить практически все компоненты матрикса (Eliceiri, Cheresh, 1999). Из литературы известно, что avP3 играет ключевую роль в миграции ГМК после повреждения сосуда, в эмбриогенезе и в канцерогенезе. Причем один из возможных механизмов усиления миграции -продукция протеиназ, которые вызывают высвобождение необходимых компонентов матрикса (Bendeck et al., 2000; Bendeck, Nakada, 2001; Dormond et al., 2001). Кроме того, как стало ясно (Larsen et al., 2006) и некоторые другие интегрины играет огромную роль в ремоделировании матрикса не только в эмбриональном развитии, но и в постнатальном периоде, выступая в роли важнейшего участника репаративных процессов в тканях богатых ЭЦМ.

Совместное исследование пролиферативного поведения и экспрессии интегринов на ГМК в онтогенезе аорты крысы не выявило существенной разницы в репертуаре экспрессии исследованных интегринов на субпопуляциях ГМК, отличающихся по пролиферативному поведению. В нашем исследовании нам не удалось увидеть отчетливой смены исследованных интегринов в зависимости от пролиферативной активности ГМК, характерной для многослойного эпителия (Carter et al., 1990b; Hertle et al., 1991). Прежде всего, это можно объяснить особенностями формирования стенки аорты. Популяция ГМК, составляющих стенку аорты складывается постепенно, и, в отличие от кожного эпителия, ГМК сами являются активными продуцентами массивного ЭЦМ и базальных мембран. Кроме того, ГМК обладают большой продолжительностью жизни (сравнимой с продолжительностью жизни животного). Эти принципиальные отличия двух типов тканей - активно обновляющейся в течение жизни (эпителий) и очень слабо обновляющейся (популяция ГМК аорты) скорее всего и служат основой тех различий, которые мы видим. ГМК синтетического фенотипа помимо высокой пролиферативной активности продуцируют различные компоненты ЭЦМ и формируют собственную базальную мембрану. ГМК сократительного фенотипа полностью одетые базальной мембраной и окруженные плотным хорошо сформированным ЭЦМ прежде всего участвуют в контроле состава матрикса. Они вовлечены в естественную перестройку матрикса и сохранение постоянства его состава Поэтому разнообразие интегринов на ГМК аорты велико, а наблюдаемые колебания незначительны даже в период активной пролиферации, так как ГМК стенки аорты, скорее всего, просто должны сохранять большое разнообразие различных по лигандной специфичности интегринов.

Кроме того, показано, что интегрины могут существовать в двух состояниях: активном и неактивном. Активация интегриновых рецепторов сопровождается их конформационными изменениями. (Оакоп е1 а1., 1995; ЬагБеп е1 а1., 2006; Такаёа е1 а1, 2007), и передачей сигнала в клетку. Инактивация ряда интегринов описана при митозе и миграции клеток, (р^апа et а1., 1990; Нупеэ, 1992; ОшпЫпег, 1996). Также наблюдается дегенерация интегринов и утилизация их самой клеткой (Такаёа е1 а1, 2007). Мы для исследования экспрессии интегринов использовали поликлональные антитела, которые выявляют как активные, так и неактивные формы интегринов. Поэтому мы не можем сказать, взаимодействует ли в данный период интегрин с матриксом или он просто находится на поверхности клетки в неактивном состоянии. Также большинство интегринов способны взаимодействовать более чем с одним компонентом матрикса. Поэтому, молено предположить, что в различные периоды морфогенеза аорты для одних и тех же интегринов лигандами могут служить разные компоненты матрикса. Мы исследовали фенотипическую картину экспрессии интегринов на ГМК аорты крысы в разные периоды развития. Вероятно, для выявления роли интегринов в регуляции пролиферации ГМК требуется более детальный анализ на уровне экспрессии генов и активации интегриновых молекул, а также исследование экспрессии других интегринов (аЗр1, а701) — рецепторов к основным компонентам ЭЦМ стенки аорты.

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