Targeting Feedback Signaling Mechanism Involved in Vascular Remodeling May Prevent PH, Study Finds

Disrupting the vascular remodeling feedback signaling loop mediated by CD146-HIF-1α can effectively prevent the development of pulmonary hypertension (PH) in mice, a study found.

This suggests that medicines that could target CD146-HIF-1α signals may represent a potential strategy to treat pulmonary arterial hypertension (PAH) and other similar disorders in humans, the researchers said.

The study, “CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension,“ was published in Nature Communications.

PAH is a type of PH that is characterized by the narrowing of the pulmonary arteries. This restricts blood flow through the lungs, and causes blood pressure to rise (hypertension). 

The narrowing of arteries is caused by a process called vascular remodeling, which involves thickening of pulmonary arterial walls, increased muscularity, and the uncontrolled growth of pulmonary artery smooth muscle cells (PASMCs). However, the underlying mechanisms of vascular remodeling remain, to some extent, unclear. 

In low-oxygen environments (hypoxia), the body naturally constricts the pulmonary arterial walls to better distribute blood flow locally. This increases the efficiency of gas exchange between blood and air. A protein called hypoxia-inducible factor 1-alpha, or HIF-1α, is responsible for activating the genes that regulate this process. 

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Chronic hypoxia is known as a cause of vascular remodeling leading to PH, which is accompanied by the aberrant activation of HIF-1α. There is evidence that the activation of this protein is enhanced by an interaction with another protein called CD146, which i is commonly present on the surface of smooth muscle cells (SMCs). 

Chinese researchers now investigated the relationship between HIF-1α and CD146. Their focus was uncovering the process of HIF-1α-guided vascular remodeling, which could potentially lead to promising PAH treatment strategies. 

First, the investigators demonstrated that increased levels of CD146 protein are associated with the severity of PH development. This was done by examining lung tissue samples over time collected from mice and rats with hypoxia-induced PH. In particular, the protein was found to be mainly present in PASMCs in remodeled pulmonary arterial walls.

Higher CD146 levels also were found to be linked to an increase in right ventricular systolic pressure. CD146 was localized to PASMCs in remodeled pulmonary arteries from PH lung samples.

Next, the team found that hypoxia-induced HIF-1α activation could trigger this increase in CD146 levels in PASMCs. When they exposed human PASMCs to different oxygen levels, the amount of CD146 was found to also rise proportionally to oxygen concentration, in a dose- and time-dependent manner. Indeed, this process was only mediated by HIF-1α. The team showed that HIF-1α was able to directly bind the DNA sequence that controls CD146 protein production. 

With further experiments, researchers were able to demonstrate that the accumulation of CD146, in turn, promoted an increase in HIF-1α through a second mediator called NF-κB.

Overall, under a hypoxia status, CD146 and HIF-1α could cross-regulate each other through a feedback loop. An increase in HIF-1α led to more CD146, which generated more HIF-1α, and so on, contributing to impaired response of PASMCs and vasculature remodeling.

Expanding on these results, the team showed that disrupting CD146-HIF-1α signals in SMCs — by genetically preventing CD146 production — would inhibit the process of pulmonary vascular remodeling in mice. Consistently, the mice that were lacking CD146 also showed reduced amounts of HIF-1α in their lungs. These results confirm that CD146 is essential for the activity of HIF-1α that is responsible for vascular remodeling. 

Finally, when the team treated PH mice with an antibody that blocks CD146 activity, the animals were protected from vascular remodeling when exposed to chronic hypoxia. These animals showed improved lung function, reduced vascular wall thickness and muscularization, and improved cardiac function in comparison with untreated mice with hypoxia-induced PH. 

All of these results together strongly suggest that targeting the cross-regulation feedback loop of CD146-HIF-1α represents a possible strategy for the treatment of PH by directly reducing the effects of vascular remodeling.

The researchers expand on this conclusion.

“Our study reveals a causative role of CD146-HIF-1α axis in pulmonary vascular remodeling. From a clinical perspective, our findings should greatly facilitate the development of potential anti-remodeling therapies for PH, and perhaps other vascular remodeling disorders,” the said.