生物谷报道：来自山东大学齐鲁医院心内科，教育部心血管重构和功能重点实验室（Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Public Health），瑞典卡罗琳学院（Karolinska Institutet）的研究人员提出angiogenic和arteriogenic因子复合蛋白治疗方法能显著提高猪心肌功能和心肌侧支功能（collaterogenesis），为心肌缺血等心脏疾病的治疗性proangiogenic/arteriogenic因子的临床发展提供了理论性指导。这一研究成果公布在《美国国家科学院院刊》（PNAS）上。
文章的通讯作者是山东大学医学院的院长张运院士，以及瑞典卡罗琳学院的曹一海博士（Yihai Cao，音译）。
心肌缺血（ischemic myocardium）是指心脏的血液灌注减少，导致心脏的供氧减少，心肌能量代谢不正常，不能支持心脏正常工作的一种病理状态。心脏的供血不是一成不变的，而是始终存在着波动，但这种波动经过机体自身调节，促使血液供需相对恒定，保证心脏正常工作。如果任何一种原因引起心肌缺血，经机体调节不能满足心脏工作需要，这就构成了真正意义上的心肌缺血。
心肌缺血治疗方案主要为选择硝酸脂类药物（如单硝酸异山梨脂或其缓释剂型），作用为扩张心脏冠状动脉，增加心肌供血；还应该服用他汀类药物（如阿伐他汀、辛伐他汀）一方面降低血浆中的胆固醇，一方面稳定动脉斑块，防止斑块脱落形成血栓，造成中风等。
其中建立功能性和稳定的侧支循环（collaterals）是恢复缺血心肌在心肌梗塞心脏功能的关键点之一。在这篇文章中，研究人员发现复合angiogenic和arteriogenic因子治疗，能高度的重建侧支网络，提高心肌灌注（myocardium）和功能。
比如复合施用FGF-2 和PDGF-BB——两种初靶定上皮细胞和脉管平滑肌细胞的因子，就能显著的增加心肌侧支的生长，使新形成的侧支网络稳定，这对于恢复心肌灌注和心肌功能意义重大。
利用不同的PDGF家族与FGF-2分别进行血管新生的实验，研究人员进一步发现PDGFR-是一种angiogenic synergism，而PDGFR-介导了脉管的稳定性。这些研究结果为心肌缺血等心脏疾病的治疗性proangiogenic/arteriogenic因子的临床发展提供了理论性的指导。
原始出处:
Published online before print July 16, 2007, 10.1073/pnas.0704966104
PNAS | July 17, 2007 | vol. 104 | no. 29 | 12140-12145
Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs
Huixia Lu*, Xinsheng Xu*, Mei Zhang*, Renhai Cao, Ebba Bråkenhielm, Changjiang Li*, Huili Lin*, Guihua Yao*, Huiwen Sun*, Lihang Qi*, Mengxiong Tang*, Hongyan Dai*, Yanen Zhang, Runyi Su, Yanwen Bi, Yun Zhang*,, and Yihai Cao,
*Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education and Public Health, Department of Cardiovascular Surgery, Qi Lu Hospital, Shandong University, Jinan 250012, Shandong Province, People's Republic of China; and Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
Communicated by Tadamitsu Kishimoto, Osaka University, Osaka, Japan, May 25, 2007 (received for review April 2, 2007)
Establishment of functional and stable collaterals in the ischemic myocardium is crucial to restoring cardiac function after myocardial infarction. Here, we show that only dual delivery of a combination of angiogenic and arteriogenic factors to the ischemic myocardium could significantly reestablish stable collateral networks and improve myocardial perfusion and function. A combination of FGF-2 with PDGF-BB, two factors primarily targeting endothelial cells and vascular smooth muscle cells, remarkably promotes myocardial collateral growth and stabilizes the newly formed collateral networks, which significantly restore myocardial perfusion and function. Using various members of the PDGF family together with FGF-2 in an angiogenesis assay, we demonstrate that PDGFR- is mainly involved in angiogenic synergism, whereas PDGFR- mediates vessel stability signals. Our findings provide conceptual guidelines for the clinical development of proangiogenic/arteriogenic factors for the treatment of ischemic heart disease.
angiogenesis | growth factor | ischemia | myocardial infarction | neovascularization
Fig. 1. Angiogenic synergism and vessel stability promoted by various members of the PDGF family alone or in combinations with FGF-2. Micropellets containing FGF-2 (A), PDGF-AA (B), PDGF-AB (C), PDGF-BB (D), PDGF-AA/FGF-2 (E and I), PDGF-AB/FGF-2 (F and J), or PDGF-BB/FGF-2 (G and K) together with the slow-release polymer sucrose aluminum octosulfate were implanted into the corneal micropockets of mice. Corneal neovascularization was examined on days 5 (A–H) and 70 (I–K) after growth factor implantation. The corneal neovascularization was quantitatively measured as clock hours and vessel lengths, and vascularization areas were calculated (H and L). Asterisks indicate the implanted pellets.
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