endothelium

Endothelium-dependent relaxation is impaired in the cerebral circulation during chronic hypertension. Dilatation of cerebral arterioles and the basilar artery in response to endothelium-dependent agonists such as acetylcholine and ADP is impaired in the chronically hypertensive rat.

 Cerebral vasodilatation in response to endothelium-independent agonists such as NO, nitroglycerin, and adenosine is not impaired during chronic hypertension, which suggests that endothelial function is impaired but vascular muscle relaxation is preserved.¹ Thus, the cAMP and cGMP mechanisms appear to be relatively normal during chronic hypertension.

Altered responses of cerebral arterioles to endothelium-dependent agonists  in chronic hypertension may impair cerebral vasodilatation in response to vasoactive substances released by platelets. It is possible that when platelets aggregate at plaques in the carotid arteries and release serotonin, impairment of endothelium-dependent responses during chronic hypertension may predispose to cerebral ischemia and stroke. Mechanisms that account for impaired endothelium-dependent relaxation during chronic hypertension are not fully defined and appear to be different in cerebral arterioles than in the basilar artery. In cerebral arterioles, this impairment may be related to release of an endothelium-derived contracting factor (EDCF) that counteracts the normal dilator effects of NO .This EDCF appears to be a prostanoid because indomethacin restores responses to Endothelium-dependent pathways of fibrogenesis play critical roles in the maintenance and progression of CKD. The mechanics of the process involve microvascular rarefaction, which itself is a result of the confluence of a multitude of pathogenic factors, such as Endo-MT, SIPS and associated abnormal secretory profiles, impaired angiogenesis and curtailed regeneration of obliterated microvascular beds, an aberrant secretome of dysfunctional EC, and enhanced degradation of endothelial glycocalyx. Strategies to alleviate endothelial dysfunction and improve the renal microcirculation must be tested in animal studies and clinical trials. Although the accumulated knowledge leaves no doubt regarding the participation of the endothelium in the pathogenesis of CKD, there remains a long translational journey to use these findings to improve outcomes in patients.

The endothelium is a monolayer of cells that lines the entire inner surface of the cardiovascular and lymphatic circulations where it controls normal physiological functions through both systemic and local regulation. Endothelial phenotypes are heterogeneous, dynamic and malleable, properties that in large- and medium-sized arteries lead to a central role in the development of focal and regional atherosclerosis. The endothelial phenotype in athero-susceptible sites is different from that in nearby athero-resistant regions. Understanding the in vivo gene, protein, and metabolic expression profiles of susceptible endothelium is, therefore, an important spatiotemporal challenge in atherosclerosis research. Recent studies have demonstrated that endoplasmic reticulum (ER) stress and the UPR are characteristics of susceptible endothelium. Here, we outline global genomic profiling, pathway analyses, and gene connectivity approaches to the identification of UPR and associated pathways as discrete markers of athero-susceptibility in arterial endothelium.