사람 심장동맥 죽상경화증에서 Angiopoietin-2의 병태생리학적 역할 = Pathophysiological Role of Angiopoietin-2 in Human Coronary Atherosclerosis

국문 초록 (Abstract)

죽상경화증에서 혈관신생(neovascularization)이 일어난다고 알려졌으나 혈관신생의 병태생리학적 역할, 발생 기전, 자극제는 여전히 명확하지 않다. Angiopoietin은 VEGF와 더불어 중요한 혈관 형성에 관련된 성장인자로 혈관신생, 혈관의 성숙, 내피의 통합유지 등에 중요한 역할을 한다. Angiopoietin-2 (Ang-2)는 다른 혈관형성인자의 존재 유무에 따라 혈관의 발아(sprouting)나 퇴행을 일으킨다고 알려져 있으나 죽상경화증에서 발현양상과 기능에 대해 연구가 아직 미비하다. 따라서 본 실험에서는 사람 심장동맥 죽상경화증에서 1) Ang-2의 분포와 발현양 2) Ang-2의 발현과 혈관의 형태학적 변화 3) Ang-2와 혈관신생의 상호관계 등의 확인을 통해 Ang-2의 병태생리학적 역할을 알아보고자 하였다.
죽상경화증을 가진 사람 심장동맥 왼쪽내림가지를 미국심장학회의 분류기준에 따라 정상, 전죽상종, 죽상종, 섬유죽상종, 복합병변으로 구분하였다. Ang-2과 관련인자의 분포는 Ang-2, CD31, α-actin, CD36, Tie-2, VEGF 항체를 이용하여 면역조직화학 염색과 western blotting을 수행하여 확인하였다. 정상심장동맥에서 Ang-2는 관찰되지 않았다. 진행된 죽상경화병변에서 Ang-2는 내피세포, 죽상판의 큰포식세포, 일부 민무늬근육세포에서 관찰되었으며, 병변의 진행에 따라 Ang-2 양이 증가하였다. 특히, Ang-2 양성반응을 나타내는 미세혈관의 수가 죽상경화증의 진행에 따라 증가하였다. 또한 혈관속막내 혈관신생은 죽상경화병변의 혈관속막 비대와 밀접한 관련이 있었다(R2 = 0.7424).
따라서 Ang-2는 사람 죽상동맥경화증에서 혈관신생 뿐만 아니라 병변의 진행에 중요한 인자로 작용할 것으로 판단된다. 이는 혈관계 질환에서 Ang-2가 중요한 잠재적인 치료표적(therapeutic target)으로서의 가능성을 제시하는 바이다.

다국어 초록 (Multilingual Abstract)

Neovascularization is well known to occur in human atherosclerotic plaques; however, its pathophysiological roles, mechanism, and stimuli still remain unclear. Angiopoietin-1 and -2 belong to another vascular-specific growth factor family and regulate angiogenesis. Angiopoietin-2 (Ang-2) provides a destabilizing signal for endothelial cells, leading to vessel regression or sprouting depending on the presence of other angiogenic
factor. But role and distribution of Ang-2 in atherosclerosis are not well known. Thus, we studied 1) the distribution and amount of Ang-2 2) the relationship between Ang-2 expression and vascular morphometrical change 3) the relationship between Ang-2 expression and neovascularization in atherosclerotic lesions.
Paraffin sections from 36 human coronary arterial segments were characterized as normal, preatheroma, atheroma,
fibroatheroma and complicated lesion according to American heart association classification. Expression of Ang-2
and related factors were examined using immunohistochemistry and western blotting with antibodies against Ang-2,
CD31 (endothelial cells), α-actin (vascular smooth muscle cells), CD36 (monocyte & macrophage), Tie-2 and VEGF.
Expression of Ang-2 was not shown in normal arterial segment. Ang-2 were localized in lumen-lining endothelium,
macrophage, some SMCs of atheromatous plaque in advanced lesion. Amount of Ang-2 was increased according to
progression of atherosclerosis.
Intraplaque microvessels had Ang-2 and VEGF positive endothelial cells and number of those in plaque increased
according to progression of disease. Intimal neovascularization is correlated with intimal thickening in atherosclerotic lesion (R2 = 0.7424).
Therefore, they suggest that Ang-2 has an important role in the progression of human coronary atherosclerosis, as well as in neovascularization. This study implicates Ang-2 as an important potential therapeutic target in vascular disease.

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