Multi-functional plant flavonoids regulate pathological microenvironments for vascular stent surface engineering

According to the World Health Organization (WHO), cardiovascular disease has become one of the leading causes of unnatural human death[1]. Balloon angioplasty and coronary stent implantation are the most common forms of atherosclerosis treatment[2]. Currently, drug-eluting stents are widely used clinically because of their low restenosis rates[3]. However, loaded drugs such as paclitaxel can not only inhibit the proliferation of smooth muscle cells (SMCs) but also suppress the growth of endothelial cells (ECs) [4]. This non-selective inhibitory effect on vessel wall cells delays endothelialization on the stent surface, increasing the risk of late thrombosis. In this context, researchers have screened multiple multi-functional biomolecules such as hyaluronic acid (HA) and heparin[5], [6], [7], [8], [9], [10] for the stent surface engineering to selectively inhibit excessive growth of SMCs while supporting the healthy growth of ECs. However, in practical applications, these biomolecules' modulatory effects faced the impact of the pathological vascular microenvironment. For example, in an oxidative stress microenvironment, HA and heparin are easily decomposed and inactivated by excessive reactive oxygen species (ROS) [11, 12].

Due to the atherosclerotic lesions and balloon dilatation-injury, the local microenvironment of stent implantation is characterized by oxidative stress, inflammation, and hyperlipidemia[13, 14]. In the oxidative stress microenvironment, excessive ROS can induce the senescence and apoptosis of ECs and SMCs, which can further cause calcification and blood coagulation, thereby promoting restenosis[15, 16]. In the inflammatory conditions, inflammatory cells aggregate and secrete inflammatory factors, such as tumor necrosis factor- α (TNF-α), to induce EC apoptosis and stimulate the migration of SMCs[17], [18], [19]. Moreover, stent also faces undesired hyperlipidemia microenvironment, which has excessive ox-LDL. The ox-LDL could induce the ECs dysfunction[20] and SMCs proliferation[21]. Furthermore, the ox-LDL could cause macrophages' conversion into foam cells, leading to higher ROS production and higher expression of inflammatory factors such as IL-6 and TNF-α, which further increased oxidative stress and inflammation[22]. Oxidative stress, inflammation, and hyperlipidemia reinforce each other through complex interactions, leading to a continuous deterioration of the vascular microenvironment, which eventually leads to in-stent restenosis (ISR) and delayed endothelialization of the stent surface[23] Therefore, to truly achieve successful vascular remodeling, the biomolecules used to modify the stent should simultaneously own the SMC-inhibiting and EC-supporting effects and the pathological microenvironment-regulation (PMR) effect.

Baicalin (BCL) is a plant-derived flavonoid compound composed of baicalein and glucoside. As a drug with various pharmacological activities, BCL has therapeutic potential for treating atherosclerosis, restenosis, and ischemia-reperfusion injury with minimal toxicity [24, 25]. Recent studies revealed that BCL could inhibit platelet-derived growth factor (PDGF)-induced proliferation of SMCs by blocking the PDGFR/MEK/ERK1/2 signaling pathway[26]. For ECs, BCL attenuates the expression of the pro-apoptotic Bax gene in ECs, leading to an increase in BCL-2 gene expression and a decrease in caspase-3 in ECs, thus reducing EC apoptosis[27]. Notably, BCL also functions in the regulation of the pathological microenvironment of atherosclerosis and vascular injury. The catechol group of BCL could scavenge ROS, such as H2O2 and superoxide anion (O2−), thus protecting ECs and exhibiting anti-oxidative stress ability[28]. BCL has been reported to exert anti-inflammatory activity by down-regulating inflammatory factors' expression in macrophages[29]. In addition, in the presence of excess ox-LDL, BCL could stimulate PPAR-γ in cells and induce LXRα expression, thereby increasing the expression of cholesterol transport proteins ABCA1 and ABCG1 BS, and preventing lipid accumulation in macrophages and foam cell formation[30]. The studies mentioned above indicate that BCL could regulate pathological microenvironments such as oxidative stress and inflammation, promote cholesterol efflux from monocytes, and inhibit the proliferation of SMCs and reduce EC apoptosis. Thus, we hypothesized that BCL could be suitable for modifying vascular stents to enhance their biological performance. However, the application of BCL to engineering the surface of vascular stents or other cardiovascular devices has rarely been reported yet.

In this study, we first prepared an amino-rich poly-dopamine-hexanediamine (PDA-HD) transition layer on the surface of the stent material, which was firmly bonded to the stent and could withstand the large deformation that occurs during stent expansion[31]. We then immobilized BCL at different densities on the stent surface via a carboxyl-amide reaction. Through in vitro and in vivo experiments, we evaluated the regulation effect of BCL on SMCs, ECs, and the pathological microenvironment. The results indicate that BCL has broad prospects for application in cardiovascular material modification.

留言 (0)

沒有登入
gif