Pathogenetic Mechanisms of Hypertension-Brain-Induced Complications: Focus on Molecular Mediators

Abstract

There is growing evidence that hypertension is the most important vascular risk factor for the development and progression of cardiovascular and cerebrovascular diseases. The brain is an early target of hypertension-induced organ damage and may manifest as stroke, subclinical cerebrovascular abnormalities and cognitive decline. The pathophysiological mechanisms of these harmful effects remain to be completely clarified. Hypertension is well known to alter the structure and function of cerebral blood vessels not only through its haemodynamics effects but also for its relationships with endothelial dysfunction, oxidative stress and inflammation. In the last several years, new possible mechanisms have been suggested to recognize the molecular basis of these pathological events. Accordingly, this review summarizes the factors involved in hypertension-induced brain complications, such as haemodynamic factors, endothelial dysfunction and oxidative stress, inflammation and intervention of innate immune system, with particular regard to the role of Toll-like receptors that have to be considered dominant components of the innate immune system. The complete definition of their prognostic role in the development and progression of hypertensive brain damage will be of great help in the identification of new markers of vascular damage and the implementation of innovative targeted therapeutic strategies.

Keywords: Toll-like receptors; cerebral complications; endothelial dysfunction; hypertension; innate immune system; neuroinflammation; oxidative stress.

Figure 1

Pathogenetic links between hypertension and stroke (from [12], modified).

Figure 2

Cerebral autoregulation curve: in patients with hypertension, this range is “right-shifted”, or in other words, the normal range mean arterial pressure in which cerebral blood flow remains constant due to cerebral autoregulation is higher. Both the lower and upper limits are shifted (from [7], modified).

Figure 3

Multiple effects of Toll-like receptors (TLRs) in vasculature cells (from [96], modified).

Figure 4

DAMPs induced activation of TLRs. Circulating DAMPs released after hypoxia, trauma and cell death lead to TLRs activation in immune cells, endothelial cells and vascular smooth muscle cells. Prolonged or excessive activation of TLRs on these cells provides a proinflammatory state, leading to endothelial dysfunction and subsequent cardiovascular disease (from [94], modified).