Correction of hypertension by normalization of endothelial levels of fibroblast growth factor and nitric oxide synthase in spontaneously hypertensive rats.

Abstract

Acidic and basic fibroblast growth factors (FGFs) share a wide range of diverse biological activities. To date, low levels of FGF have not been correlated with a pathophysiologic state. We report that blood vessels of spontaneously hypertensive rats are shown to be associated with a marked decrement in endothelial basic FGF content. This decrement correlates both with hypertension and with a decrease in the endothelial content of nitric oxide synthase. Restoration of FGF to physiological levels in the vascular wall, either by systemic administration or by in vivo gene transfer, significantly augmented the number of endothelial cells with positive immunostaining for nitric oxide synthase, corrected hypertension, and ameliorated endothelial-dependent responses to vasoconstrictors. These results suggest an important role for FGFs in blood pressure homeostasis and open new avenues for the understanding of the etiology and treatment of hypertension.Acidic and basic fibroblast growth factors (aFGF and bFGF, respectively) are homologous polypeptides (55% amino acid sequence identity) that were first isolated on the basis of their ability to induce mitogenesis on murine BALB/c 3T3 fibroblasts. aFGF was also isolated as an endothelial cell growth factor. It has become progressively evident that FGFs are mitogens of remarkably broad mitogenic activity. In fact, they induce cell division in almost all the mesoderm-and neuroectoderm-derived cell lines in culture. It has also been shown that these proteins share diverse hormone-like activities, including vasodilation. So far, no clear-cut differences have been found in the biological spectrum of activities of these polypeptides. FGFs have been also called heparin binding growth factors because of their characteristic high affinity for heparin and heparan sulfate (for reviews, see refs. 1-3). It has been shown in rats and rabbits that FGFs cause an acute vasodilation when they are administered systemically at the level of subnanomoles per kilogram of body weight (4). FGF-induced vasorelaxation is partially abrogated by inhibitors of the synthesis of nitric oxide (NO). Endothelial-derived NO is one of the most important regulators of vascular tone (5). The synthesis of NO is catalyzed in endothelial cells by a distinct, constitutive NO synthase (ecNOS; ref. 6).The spontaneously hypertensive (SH) rat strain was developed by Okamoto and Aoki (7) by mating a couple of SH rats from the normotensive Wistar-Kyoto (WKY) strain. In SH rats, hypertension develops quite abruptly between weeks 5 and 20 and worsens as they age. The developmental course of hypertension makes SH rats an adequate model of essential hypertension (8, 9). SH rats have been, consequently, the object of numerous studies. Deep neuroendocrine alterations that could cause blood pressure elevation have been described in these rats. Thus, alterations in the levels of vasoactive intestinal polypeptide, vasopressin, adrenergic amines, and angiotensin II have been reported (10-14). On the other hand, vascular hyp...

Syndecan-4 modulates basic fibroblast growth factor 2 signaling in vivo

“…The ability of FGF2 to induce NO release is well documented (2,11). Whereas in the case of VEGF, NO release involves AKT-1-dependent activation of eNOS on Ser 1177 (3,5,15), no similar mechanism for FGF2 has been established.…”

Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

“…In a model of genetic hypertension in the rat, the spontaneously hypertensive rat (SHR), abnormalities in synthesis of NO, expression of the NO-synthesizing enzymes, or both have been described both in vitro and in vivo, but with conflicting results. Thus, several studies have been performed to provide evidence of impaired vasodilation in response to acetylcholine, an effect mediated by endothelium-derived relaxing factor or NO, decreased eNOS expression, or decreased NO synthesis in SHR (5)(6)(7)(8)(9)(10)(11). These abnormalities are present as early as 5 wk of age, a period before the development of hypertension (7).…”

Cardiovascular gene delivery: The good road is awaiting☆

“…For example, VEGF has been tumorigenic [225,226], and FGF has been associated with proliferative membranous nephropathy in mouse models [227][228][229]. Also, the induction of hypotension after delivery of these growth factors is a concern because VEGF can cause systemic hypotension and edema of the lower extremity clinically [230,231] and FGF plays an essential role in the prevention of hypertension [232]. Most of these concerns have not been reported in clinical trials to date.…”