Abstract
Pathological angiogenesis, as exhibited by aberrant vascular structure and function, has been well deemed to be a hallmark of cancer and various ischemic diseases. Therefore, strategies to normalize vasculature are of potential therapeutic interest in these diseases. Recently, identifying bioactive compounds from medicinal plant extracts to reverse abnormal vasculature has been gaining increasing attention. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza, has been shown to play significant roles in improving blood circulation and delaying tumor progression. However, the underlying mechanisms responsible for the therapeutic effects of Tan IIA are not fully understood. Herein, we established animal models of HT-29 human colon cancer xenograft and hind limb ischemia to investigate the role of Tan IIA in regulating abnormal vasculature. Interestingly, our results demonstrated that Tan IIA could significantly promote the blood flow, alleviate the hypoxia, improve the muscle quality, and ameliorate the pathological damage after ischemic insult. Meanwhile, we also revealed that Tan IIA promoted the integrity of vascular structure, reduced vascular leakage, and attenuated the hypoxia in HT-29 tumors. Moreover, the circulating angiopoietin 2 (Ang2), which is extremely high in these two pathological states, was substantially depleted in the presence of Tan IIA. Also, the activation of Tie2 was potentiated by Tan IIA, resulting in decreased vascular permeability and elevated vascular integrity. Mechanistically, we uncovered that Tan IIA maintained vascular stability by targeting the Ang2-Tie2-AKT-MLCK cascade. Collectively, our data suggest that Tan IIA normalizes vessels in tumors and ischemic injury via regulating the Ang2/Tie2 signaling pathway.
Highlights
It has been well recognized that blood vessels mainly including arteries, veins, and capillaries are composed of endothelial cells (ECs), with pericytes and smooth muscle cells to form a complete structure in normal tissues
In the assessment of ischemic damage, our results showed that the mice treated with Tanshinone IIA (Tan IIA) did not exhibit obvious necrosis, and the score was between 0 and 2 while the mice treated with 0.3% CMC-Na were scored 2–4 at day 21 postsurgery (Figure 1(d))
Our results deciphered that intragastric administration of Tan IIA could strikingly reinforce the blood perfusion recovery, which was potentially owing to the improved formation of functional blood vessels in the ischemic hind limbs
Summary
It has been well recognized that blood vessels mainly including arteries, veins, and capillaries are composed of endothelial cells (ECs), with pericytes and smooth muscle cells to form a complete structure in normal tissues. Vascular morphology is commonly impaired, and these defective vessels cannot participate in the blood circulation system and fail to supply oxygen and nutrients to the ischemic lesions for the recovery [5]. When vascular ECs undergo a tubular shape to form a lumen and mature into functional vessels, they can provide new oxygenated blood supply for hypoxic tissues [6]. Given the fact that tumors and ischemic diseases share similar pathological features in light of vascular abnormalities, reversing immature and unstable blood vessels back to normal blood vessels appears to be an effective route for the treatments of the diseases
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