Occlusive Lung Arterial Lesions in Endothelial-Targeted, Fas-Induced Apoptosis Transgenic Mice

Abstract

Pulmonary arterial hypertension (PAH) is a lethal disease that is characterized by functional and structural abnormalities involving distal pulmonary arterioles that result in increased pulmonary vascular resistance and ultimately right heart failure. In experimental models of pulmonary hypertension, endothelial cell (EC) apoptosis is a necessary trigger for the development of obliterative lung arteriopathy, inducing the emergence of hyperproliferative and apoptosis-resistant vascular cells. However, it has not been established whether EC apoptosis is sufficient for the induction of complex lung arteriolar lesions. We generated a conditional transgenic system in mice to test the hypothesis that lung endothelial cell apoptosis is sufficient to induce a PAH phenotype. The Fas-induced apoptosis (FIA) construct was expressed under the control of endothelial-specific Tie2 promoter (i.e., EFIA mice), and administration of a small molecule dimerizing agent, AP20187, resulted in modest pulmonary hypertension, which was associated with obliterative vascular lesions localized to distal lung arterioles in a proportion of transgenic mice. These lesions were characterized by proliferating cells, predominantly CD68 macrophages. Although endothelial cell apoptosis was also seen in the kidney, evidence of subsequent arteriopathy was seen only in the lung. This model provides direct evidence that lung endothelial cell apoptosis acts as a trigger to initiate a PAH phenotype and provides initial insight into the potential mechanisms that underlie a lung-specific arterial response to endothelial injury.

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

“…Indeed, increased pulmonary EC injury and apoptosis are known to act as triggers to initiate PAH (29)(30)(31). Consistent with this notion, we show that pretreatment of rats with dasatinib (at a dose of 1× or 10×), but not imatinib, increases MCT-and chronic hypoxia-induced PH.…”

Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis

“…However, confirmation of the findings with monocytes from patients with SSc is warranted. Given that M2 macrophages are a rich source of profibrotic mediators34 and M2 macrophages have been shown to strongly affect the outcome in various preclinical models of fibrosis39 and that changes in M2 mRNA signature have recently been linked to clinical outcomes in patients with SSc,20 40 the effects of nintedanib on M2 polarisation might significantly contribute to the antifibrotic effects of nintedanib in vivo and may be of direct clinical relevance.…”

“…At the molecular level, inhibition of PDGFR with impaired proliferation of vascular smooth muscle cells is likely to play a central role for the beneficial effects of nintedanib on PAH. As recent data provide elegant evidence that apoptosis of endothelial cell may promote PAH,39 further studies should investigate whether the positive effects of nintedanib on the histological features of PAH are in part mediated by inhibition of pulmonary vascular EC apoptosis.…”

Role of FoxO1 and apoptosis in pulmonary vascular remolding in a rat model of chronic thromboembolic pulmonary hypertension

“…Several possible mechanisms have been proposed including the following: apoptosis induces the defluvium of endothelial cells and the collapse of pre-capillary arterioles, thereby enhancing pulmonary artery resistance; apoptotic endothelial cells lose their suppressive effect on smooth muscle cell proliferation, leading to pulmonary remolding; the apoptosis-resistant endothelial cells are enriched by the apoptotic process 24, 25 . In the present study, levels of the mRNA encoding the pro-apoptotic protein Bad gradually increased following repeated embolism.…”