活跃的内皮无活化超性:由氧化驱动的cAMP/Epac1信号传输的作用
Mauricio A Lillo1, Pía C Burboa1, Walter N Durán1
1Department of Pharmacology, Physiology and Neuroscience, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
Journal of cardiovascular development and disease
|September 26, 2025
概括
氧化 (NO) 启动一个延迟的信号级联,在炎症期间积极恢复内皮屏障功能. 这种协调的过程增强了屏障的完整性,并为血管疾病提供治疗点.
科学领域:
- 血管生物学和病理生理学
- 细胞信号和细胞骨动力学
- 炎症和免疫学 炎症和免疫学
背景情况:
- 内皮膜的透性是炎症和血管疾病的关键特征,如败血症和ARDS.
- 屏障恢复传统上被视为被动的,但现在被理解为一个活跃的,内皮驱动的过程.
- 之前的研究已经确定了与屏障修复有关的离散信号分子和途径.
研究的目的:
- 为内皮质屏障恢复的活跃,协调机制提供统一的框架.
- 将氧化 (NO) 的作用从屏障破坏者转变为屏障恢复的触发者.
- 在血管病理中确定加速内皮封闭的潜在治疗点.
主要方法:
- 综合分析来自多个研究小组的机械洞察力.
- 对内皮质屏障功能的分子,结构和转化数据的审查.
- 专注于包括cAMP/Epac1,Rap1/Rac1,VASP,eNOS,PP2A和KLF2.2在内的信号通路.
主要成果:
- 氧化 (NO) 启动了一个延迟的cAMP/Epac1级联,协调屏障恢复.
- 这种级联涉及协调的细胞骨重塑,结节定和转录程序.
- 这个过程形成了一个多层次的"无活化"程序,即使在持续的炎症中,也能恢复屏障的完整性.
结论:
- 内皮膜屏障的恢复是一个活跃的,NO启动的,协调的信号过程.
- 针对Epac1,Rap1/Rac1,RhoA/ROCK,PP2A和KLF2的治疗策略可以促进内皮密封.
- 这些机制为预防动脉样硬化和治疗急性微血管综合征提供了新的辅助方法.
相关概念视频
Nitric Oxide Signaling Pathway
6.2K
Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure...
6.2K
Regulation of Angiogenesis and Blood Supply
3.3K
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
3.3K
cAMP-dependent Protein Kinase Pathways
8.3K
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
8.3K
Paracrine Signaling
59.4K
Paracrine signaling allows cells to communicate with their immediate neighbors via secretion of signaling molecules. Such a signal can only trigger a response in nearby target cells because the signal molecules degrade quickly or are inactivated if not taken up. Prominent examples of paracrine signaling include nitric oxide signaling in blood vessels, synaptic signaling of neurons, the blood clotting system, tissue repair/wound healing, and local allergic skin reactions. Nitric oxide as a...
59.4K
Amplifying Signals via Enzymatic Cascade
17.5K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
17.5K
GPCRs Regulate Adenylyl Cylase Activity
7.3K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
7.3K
![Development and Characterization of In Vitro Microvessel Network and Quantitative Measurements of Endothelial [Ca2+]i and Nitric Oxide Production](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F54014.jpg&w=3840&q=50)

