CD40L promotes development of acute aortic dissection via induction of inflammation and impairment of endothelial cell function

Abstract

Acute aortic dissection is one of the most lethal cardiovascular disease. The major histopathological feature of AAD is medial degradation, especially breakdown of elastin and collagen. However, the underlying mechanism remains a mystery. Platelets expressed CD40 Ligand (CD40L) is recently recognised as a key effector of cardiovascular disease development through its pro-inflammatory effect. To clarify the role of CD40L in AAD, we examined level of CD40L in human blood serum samples and found that it is significantly higher in AAD patients compared with healthy subjects (26.8±5.52 ng/mL versus 13.4±4.00 ng/mL). To further investigate if CD40L is involve in the development of AAD, we applied β-aminopropionitrile (BAPN) induced mouse model of AAD. Consistent with the human data, circulating CD40L in AAD mice much higher than normal mice (148.40±75.96 pg/mL versus 44.09±19.65 pg/mL). Meanwhile, multiple pro-inflammatory chemokines significantly increased in AAD mice. Importantly, the CD40L-/- mice treated with BAPN did not develop these phenotypes. Lastly, we confirmed that endothelial cells migration was significantly inhibited by CD40L, suggesting impaired recovery from intimal injury. In summary, we found that CD40L promoted AAD development through its pro-inflammatory effects and inhibition of endothelial cell function.

miR-27a regulates vascular remodeling by targeting endothelial cells' apoptosis and interaction with vascular smooth muscle cells in aortic dissection

“…Moreover, suppression of EC apoptosis induces inflammation in aorta 47 . ECs dysfunction promotes AD development through pro-inflammatory effect 14. VSMC dysfunction can be stimulated by endothelial injury signals, and participates in the pathogenesis of vascular diseases 49.…”

“…The focus of previous studies related to the pathogenesis of AD has been on VSMCs 12-13. Although some studies have found abnormal appearance of ECs in AD 14-15, the role of ECs in the pathogenesis of AD remains largely unknown. However, endothelial dysfunction is predictive of vascular events and long-term clinical outcome 16-18.…”

Angiotensin type 1 receptor regulates yes‑associated protein in vascular endothelial cells

“…They are important in regulating blood flow, and thus, are involved in numerous physiological processes (6). Inflammation can result in VEC dysfunction and further promote AD progression (7). Angiotensin II (Ang II) is the major effector peptide of the renin-angiotensin system (RAS), which induces vasoconstriction, hypertrophy and extracellular remodeling via the angiotensin type 1 receptor (AT1R) (8).…”

The Role of Macrophages in Aortic Dissection

“…AD is a disease in which the structure of the aortic wall is degraded, eventually causing the intima to rupture, with blood entering the media to form a FL (Han et al, 2018). Macrophages respond mainly to Ang II, and the recruitment, activity and secretion of macrophages in the aortic wall trigger and maintain inflammation there (Dimmeler et al, 1997;Daugherty et al, 2000;Schluter and Wenzel, 2008).…”

“…Epidemiological surveys have shown that the incidence of thoracic AD is 3-4 per 100,000 individuals per year (Olsson et al, 2006;Kochanek et al, 2011). AD is defined as blood flow that enters the aortic media through intimal tears, followed by formation of a true lumen (TL) and a false lumen (FL) with or without communication (Han et al, 2018). Computed tomography angiography (CTA) images of normal aorta and AD in patients from our center are shown in Figure 1.…”