Kiss Attila, Nadasy Gyorgy L, Fees Alexander, Arnold Zsuzsanna, Aykac Ibrahim, Dostal Christopher, Szabó Gábor T, Szabó Petra Lujza, Szekeres Maria, Pokreisz Peter, Hunyady Laszlo, Podesser Bruno K
Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria.
Department of Physiology, Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary.
Rev Cardiovasc Med. 2023 Jan 4;24(1):6. doi: 10.31083/j.rcm2401006. eCollection 2023 Jan.
Geometrical alterations in the coronary resistance artery network and the potential involvement of Tenascin C (TNC) extracellular matrix protein were investigated in diabetic and control mice.
Diabetes was induced by streptozotocin (STZ) injections (n = 7-11 animals in each group) in Tenascin C KO (TNC KO) mice and their Wild type (A/J) littermates. After 16-18 weeks the heart was removed and the whole subsurface network of the left coronary artery was prepared (down to branches of 40 m outer diameter), pressure-perfused and studied using video-microscopy. Outer and inner diameters, wall thicknesses and bifurcation angles were measured on whole network pictures reconstructed into collages at 1.7 m pixel resolutions.
Diabetes induced abnormal morphological alterations including trifurcations, sharp bends of larger branches, and branches directed retrogradely ( 0.001 by the test). Networks of TNC KO mice tended to form early divisions producing parallelly running larger branches ( 0.001 by the probe). Networks of coronary resistance arteries were substantially more abundant in 100-180 m components, appearing in 2-5 mm flow distance from orifice in diabetes. This was accompanied by thickening of the wall of larger arterioles ( 220 m) and thinning of the wall of smaller (100-140 m) arterioles ( 0.001). Blood flow should cover larger distances in diabetic networks, but interestingly STZ-induced diabetes did not generate further geometrical changes in TNC KO mice.
Diabetes promotes hypertrophic and hypotrophic vascular remodeling and induces vasculogenesis at well defined, specific positions of the coronary vasculature. TNC plays a pivotal role in the formation of coronary network geometry, and TNC deletion causes parallel fragmentation preventing diabetes-induced abnormal vascular morphologies.
研究糖尿病小鼠和对照小鼠冠状动脉阻力动脉网络的几何形态改变以及腱生蛋白C（TNC）细胞外基质蛋白的潜在作用。
通过向腱生蛋白C基因敲除（TNC KO）小鼠及其野生型（A/J）同窝小鼠注射链脲佐菌素（STZ）诱导糖尿病（每组7 - 11只动物）。16 - 18周后取出心脏，制备左冠状动脉的整个表面下网络（直至外径40μm的分支），进行压力灌注并使用视频显微镜进行研究。在以1.7μm像素分辨率重建为拼贴画的整个网络图片上测量外径和内径、壁厚和分支角度。
糖尿病诱导了异常的形态学改变，包括三叉分支、较大分支的急剧弯曲以及逆行分支（经检验P < 0.001）。TNC KO小鼠的网络倾向于形成早期分支，产生平行延伸的较大分支（经探针检验P < 0.001）。在糖尿病状态下，冠状动脉阻力动脉网络在100 - 180μm的血管成分中显著增多，出现在距开口2 - 5mm的血流距离处。这伴随着较大小动脉（>220μm）壁增厚和较小小动脉（100 - 140μm）壁变薄（P < 0.001）。在糖尿病网络中血流应覆盖更大的距离，但有趣的是，STZ诱导的糖尿病在TNC KO小鼠中未产生进一步的几何形态改变。
糖尿病促进肥厚性和萎缩性血管重塑，并在冠状动脉系统的明确、特定位置诱导血管生成。TNC在冠状动脉网络几何形态的形成中起关键作用，TNC缺失导致平行性碎裂，可预防糖尿病诱导的异常血管形态。
