Hypertension is the name given to a state of high blood pressure. The onset of this condition typically progresses over time, as aging or lifestyle choices cause slowly increasing dysfunction in the systems of regulation and feedback that control blood pressure. A number of mechanisms are involved in determination of blood pressure, such as the kidney's regulation of the volume of fluid in blood, the ability of blood vessels to contract and dilate to change the overall volume of the vascular system, and the pace at which the heart beats. The important processes of regulation are known as the renin-angiotensin-aldosterone system, in which signals pass back and forth from kidney to vasculature and other involved organs, including liver and brain.
One of the ways in which animal models of hypertension are created is to break the normal regulation of blood pressure by introducing excess angiotensin II, as increased angiotension II is seen in many cases of human hypertension. In today's open access paper, researchers note that inducing hypertension in this way produces dysfunction in cells in the vasculature and brain before blood pressure increases. This suggests that even the early stages of hypertension cause harm that contributes to the well-established correlation between hypertension and cognitive decline, and in a different way than this relationship is commonly considered, not via increased structural damage to the brain resulting from a greater pace of rupture of microvessels.
Hypertension Affects the Brain Much Earlier than Expected
Hypertension impairs blood vessels, neurons, and white matter in the brain well before the condition causes a measurable rise in blood pressure, according to a new preclinical study. Patients with hypertension have a 1.2 to 1.5-fold higher risk of developing cognitive disorders than people without the condition, but exactly why is not understood. While many current hypertension medications successfully lower high blood pressure, they often show little or no effect on brain function. This suggests blood vessel changes could cause damage independently of the elevated pressure associated with hypertension.
To induce hypertension in mice, the researchers administered the hormone angiotensin, which raises blood pressure, mimicking what happens in humans. Then, they looked at how different types of brain cells were impacted three days later (before blood pressure increased) and after 42 days (when blood pressure was high, and cognition was affected). At day three, gene expression dramatically changed in three cell types: endothelial cells, interneurons, and oligodendrocytes. Endothelial cells, which line the internal surface of blood vessels, aged prematurely with lower energy metabolism and senescence, indicating they stopped dividing. The researchers also observed early signs of a weakened blood-brain barrier, which regulates the influx of nutrients into the brain and keeps out harmful molecules.
Hypertension-induced neurovascular and cognitive dysfunction at single-cell resolution
Hypertension is a leading cause of cognitive impairment, attributed to cerebrovascular insufficiency, blood-brain barrier disruption, and white matter damage. However, how hypertension affects brain cells remains unclear. Using single-cell RNA sequencing (scRNA-seq) in a mouse model of hypertension induced by angiotensin II, a peptide involved in human hypertension, we mapped neocortical transcriptomic changes before (3 days) and after (42 days) onset of neurovascular and cognitive deficits. Surprisingly, endothelial transport disruption and senescence, stalled oligodendrocyte differentiation, and interneuronal hypofunction and network imbalance emerged after 3 days, attributable to angiotensin II signaling. By 42 days, when cognitive impairment becomes apparent, deficits in myelination and axonal conduction, as well as neuronal mitochondrial dysfunction, developed.
These findings reveal a previously unrecognized early vulnerability of endothelial cells, interneurons, and oligodendrocytes, and they provide the molecular bases for subsequent neurovascular dysfunction and cognitive impairment in hypertension. These data constitute a valuable resource for future mechanistic studies and therapeutic target validation.
View the full article at FightAging
