The Local Regulation of Vascular Function: From an Inside-Outside to an Outside-Inside Model

Abstract

Our understanding of the regulation of vascular function, specifically that of vasomotion, has evolved dramatically over the past few decades. The classic conception of a vascular system solely regulated by circulating hormones and sympathetic innervation gave way to a vision of a local regulation. Initially by the so-called, autacoids like prostacyclin, which represented the first endothelium-derived paracrine regulator of smooth muscle. This was the prelude of the EDRF-nitric oxide age that has occupied vascular scientists for nearly 30 years. Endothelial cells revealed to have the ability to generate numerous mediators besides prostacyclin and nitric oxide (NO). The need to classify these substances led to the coining of the terms: endothelium-derived relaxing, hyperpolarizing and contracting factors, which included various prostaglandins, thromboxane A2, endothelin, as well numerous candidates for the hyperpolarizing factor. The opposite layer of the vascular wall, the adventitia, eventually and for a quite short period of time, enjoyed the attention of some vascular physiologists. Adventitial fibroblasts were recognized as paracrine cells to the smooth muscle because of their ability to produce some substances such as superoxide. Remarkably, this took place before our awareness of the functional potential of another adventitial cell, the adipocyte. Possibly, because the perivascular adipose tissue (PVAT) was systematically removed during the experiments as considered a non-vascular artifact tissue, it took quite long to be considered a major source of paracrine substances. These are now being integrated in the vast pool of mediators synthesized by adipocytes, known as adipokines. They include hormones involved in metabolic regulation, like leptin or adiponectin; classic vascular mediators like NO, angiotensin II or catecholamines; and inflammatory mediators or adipocytokines. The first substance studied was an anti-contractile factor named adipose-derived relaxing factor of uncertain chemical nature but possibly, some of the relaxing mediators mentioned above are behind this factor. This manuscript intends to review the vascular regulation from the point of view of the paracrine control exerted by the cells present in the vascular environment, namely, endothelial, adventitial, adipocyte and vascular stromal cells.

Keywords: EDCF; EDHF; PVAT-derived NO; adventitia; endothelium-derived NO; perivascular adipose tissue; prostaglandins.

FIGURE 1

Functional anatomy of a vessel showing the three classic tunicae plus the fourth proposed layer, PVAT or tunica adiposa. The paracrine substances produced by each layer are depicted. Prostacyclin (PGI₂), thromboxane A₂ (TXA₂), prostaglandin E₂ (PGE₂), endothelium-derived hyperpolarizing factors (EDHFs), endothelin-1 (ET-1), angiotensin II (AT II), adipose-derived relaxing factor (ADRF).

FIGURE 2

Hanasaki and Arita’s early vision of prostaglandin’s action on smooth muscle cell receptors was a prelude of much research on the role of different prostaglandins, and most especially prostacyclin, acting as a vasoconstrictor and, thereby, functioning as an endothelium-derived contracting factor. Thromboxane A2 (TXA₂), prostaglandins (PGs), smooth muscle cell (SMC). Modified from Hanasaki and Arita (1989).

FIGURE 3

In physiological conditions, eNOS is expressed in PVAT and produces NO. PVAT-derived NO diffuses into the capillaries protecting endothelial function. In pathological conditions, the production of PDNO is compromised due to superoxide overproduction in PVAT, which is formed by NADPH oxidase and uncoupled eNOS. Activity of NADPH oxidase is increased in this tissue. Overproduction of superoxide anion by uncoupled eNOS or NADPH oxidase leads to peroxynitrite formation, which in turn produces oxidation of BH4 to BH2, an essential cofactor of eNOS. PVAT: perivascular adipose tissue, VSMC: vascular smooth muscle cells; EC: endothelial cells; eNOS: endothelial isoform of nitric oxide synthase; NO: nitric oxide; PDNO: PVAT-derived NO; ONOO^-: peroxinitrite; O₂^-: superoxide anion; L-Arg: L-Arginine; BH4: tetrahydrobiopterin; BH2: dihydrobiopterin; p67^phox, p47 and p22 and NOX2: NADPH oxidase subunits.

FIGURE 4

Modern patterns of “outside-to-inside” and “inside-to-outside” communication exhibited by PVAT adipocyte/sympathetic nerve endings-endothelial-smooth muscle cell- interactions. The three-way crosstalk so far discovered involves endothelium-derived NO (EDNO) on the luminal side, and on the perivascular side: angiotensin 1-7 (AT1-7), leptin, TNFα, reactive oxygen species (ROS), adiponectin, NO synthase (NOS), PVAT-derived NO (PDNO) and noradrenaline (NA) from the nerve endings.