Revealing the role of angiotensin II in pulmonary arterial hypertension

Angiotensin II and pulmonary arterial hypertension: calcium signalling nanodomains provide the locks and the keys to smooth muscle contraction, relaxation and gene expression

In pulmonary arterial hypertension (PAH), higher levels of a hormone called angiotensin II promote PAH because they cause the smooth muscle cells that line the wall of the lung arteries to contract, raising the pressure in these vessels. Higher angiotensin II levels also cause gene changes that affect the muscle cells and make the disease worse. Smooth muscle cells have a storage compartment called the sarcoplasmic reticulum that holds a pool of calcium. Angiotensin II leads to release of this calcium, triggering signals in the cells that control many different functions, including when they should contract, and which genes they use, or a combination of both. Different calcium signals produced by angiotensin II are partly responsible for helping the cell to select the right function that is needed, but we do not understand how. Professor Mark Evans at the University of Edinburgh believes that angiotensin II regulates the cell by using strategically positioned ‘gates’ (called calcium ion pumps and release channels) that cause calcium to be released from different regions of the sarcoplasmic reticulum into different parts of the cell, thereby affecting cell function. The BHF has now awarded Professor Evans a grant to use state-of-the-art microscopy techniques, including 3D, to find out precisely where the different gates that angiotensin II uses are located on the sarcoplasmic reticulum. He will find out which ones control muscle contraction and relaxation, which induce gene changes and reveal how angiotensin II controls them. This research will reveal more about how angiotensin II has its effects on calcium signals in lung artery muscle cells, and how it might therefore promote pulmonary hypertension. It may reveal clues for new ways to treat the disease in the future.