A recent study suggested that vascular stiffening induces the development of pulmonary arterial hypertension (PAH). The findings were described in the article, “Distal vessel stiffening in an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension,” recently published in the journal JCI Insight.
PAH is a disease of the pulmonary vasculature, characterized by a progressive pulmonary arterial (PA) stiffening. The condition can be idiopathic, heritable, or associated with other diseases. Pulmonary arterial stiffness progression is correlated with an increased mortality in PAH patients. However, it was not known if pulmonary arterial stiffness was a consequence or a cause of PAH.
Laura Fredenburgh and her team from Brigham and Women’s Hospital in Boston showed, for the first time, at microscopic level (in both human cells and experimental mouse model), that vascular matrix stiffening is an early distal event that affects the surrounding resident vascular cells. The result is the secretion of more stiff matrix by those cells, contributing to PAH progression.
The study showed that pulmonary arterial stiffening has a significant impact, namely in pulmonary artery endothelial cells (PAEC) and pulmonary artery smooth muscle cells (PASMC). The matrix stiffness induces significant cell proliferation, reduction of apoptosis, strong cell contraction, and secretion of an altered matrix composition that is stiff, which will in turn affect other surrounding cells. This is a feedback loop responsible for the progression of PA stiffening, which in turn contributes to the development of PAH.
The Boston team observed that matrix stiffness downregulates the expression of COX-2 in both PASMC and PAEC, leading to a decrease of prostanoids secretion in PASMC. However, the administration of prostacyclin (a subclass of prostanoids) attenuated the features acquired by PASMC in a stiff matrix environment.
In vivo studies using a mouse model also showed that administration of treprostinil (an analog of prostacyclin) inhibited pulmonary arterial stiffness and prevented the development of PAH disease.
More studies need to be performed to better understand the impact of the administration of different prostanoids in cells expressing prostanoid receptors. Nevertheless, the authors of the study suggested that prostanoid-based therapy, which is administrated to treat severe PAH, should be extended early in the disease to stop the amplification of pulmonary arterial stiffness, and consequently, the progression of PAH.