Idiopathic pulmonary arterial hypertension (PAH) is a fatal and progressive disease. Pulmonary vasoconstriction due to pulmonary arterial smooth muscle cell (PASMC) contraction and pulmonary arterial remodeling due to PASMC proliferation are causes for increased pulmonary vascular resistance in patients with PAH. We and others observed upregulation of TRPC6 channels in PASMC from patients with PAH. An increase in cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC triggers PASMC contraction and vasoconstriction, while Ca2+-dependent activation of PI3K/AKT/mTOR pathway is pivotal for cell proliferation and gene expression. Despite evidence supporting a pathological role of TRPC6, no selective and orally bioavailable TRPC6 blocker has yet been developed and tested for treatment of PAH. We sought to investigate whether block of receptor-operated Ca2+ channels or TRPC6 can reverse established PH in mice via inhibiting Ca2+-dependent activation of AKT/mTOR signaling. Here we report that intrapulmonary application of 2-aminoethyl diphenyl borniate (2-APB), a non-selective blocker of cation channels or BI-749237, a selective blocker of TRPC6, significantly and reversibly inhibited acute hypoxic pulmonary vasoconstriction. Intraperitoneal injection of 2-APB significantly attenuated the development of PH and partially reversed established PH. Oral gavage of the selective TRPC6 blocker BI-749237 reversed established PH by 50% via regression of pulmonary vascular remodeling. Furthermore, 2-APB and BI-749237 both inhibited PDGF- and serum-mediated phosphorylation of AKT and mTOR in PASMC. These results indicates that the receptor-operated and mechanosensitive TRPC6 channel is a good target for developing novel treatment for PAH. BI-749237, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH.

Concentric pulmonary vascular wall thickening due partially to increased PASMC proliferation contributes to elevating PVR in patients with pulmonary hypertension (PH). While pulmonary vasoconstriction may be an early contributor to increasing PVR, the transition of contractile PASMCs to proliferative PASMCs may play an important role in the development and progression of pulmonary vascular remodeling in PH. A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) is a trigger for PASMC contraction and proliferation. Here we report that upregulation of Piezo1, a mechanosensitive cation channel, is involved in the contractile-to-proliferative phenotypic transition of PASMCs and development of pulmonary vascular remodeling. By comparing freshly isolated PA (contractile PASMCs) and primary cultured PASMCs in growth medium (proliferative PASMCs), we found that Piezo1, Notch2/3 and CaSR protein levels were significantly higher in proliferative PASMCs than in contractile PASMCs. Upregulated Piezo1 was associated with an increase in expression of PCNA, a marker for cell proliferation, whereas downregulation (with siRNA) or inhibition (with GxMTx4) of Piezo1 attenuated PASMC proliferation. Furthermore, Piezo1 in the remodeled PA from rats with experimental PH was upregulated in comparison to PA from control rats. These data indicate that PASMC contractile-to-proliferative phenotypic transition is associated with the transition or adaptation of membrane channels and receptors. Upregulated Piezo1 may play a critical role in PASMC phenotypic transition and PASMC proliferation. Upregulation of Piezo1 in proliferative PASMCs may likely be required to provide sufficient Ca2+ to assure nuclear/cell division and PASMC proliferation, contributing to the development and progression of pulmonary vascular remodeling in PH.

A true pulmonary arterial aneurysm is the dilation of all three vascular walls in a pulmonary artery. True pulmonary arterial aneurysms are very rare, and the relatively minor cases on this topic present with symptoms pertaining to the causes of trauma, Behçet’s disease, pulmonary vasculitis, granulomatous lung infections, and cartilage instability. A rupture of the pulmonary arterial aneurysm can be life-threatening and often requires surgical repair. Our case presents a 70-year-old male who was referred to pulmonary clinic for evaluation of an asymptomatic, incidental finding in his right lower lobe that was considered to represent a pulmonary nodule based on its presentation on computed tomography imaging. The referring provider had requested a possible biopsy. Before proceeding with a biopsy, the presence of the pulmonary aneurysm was confirmed only after the fluorodeoxyglucose-positron emission tomography scan and a computed tomography angiography were performed. Our case illustrates the importance of including pulmonary aneurysm in the differential during work-up of a pulmonary nodule, as diagnostic sampling could have been detrimental.

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