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Platelets, growth factors, and vascular smooth-muscle cells in hypertension and diabetes
N Mikhail1, N Fukuda, J Tremblay
1Centre de Recherche, Hôtel-Dieu de Montréal, Université de Montréal, Quebec, Canada.
Insights
Vascular smooth muscle cells (VSMCs) from hypertensive rats show abnormal growth patterns, suggesting a primary role in hypertension pathogenesis. Platelet growth-promoting activity is altered in hypertension and diabetes.
Area of Science:
- Vascular Biology
- Cellular Physiology
- Hypertension Research
Background:
- Inappropriate vascular smooth-muscle cell (VSMC) growth is central to hypertension and diabetic macroangiopathy.
- Platelets regulate vessel wall homeostasis and contain crucial growth factors.
- Platelet function abnormalities, including enhanced activity and altered aggregation, are observed in diabetes and hypertension.
Purpose of the Study:
- To investigate intrinsic growth anomalies in VSMC from spontaneously hypertensive rats (SHRs) compared to normotensive Wistar-Kyoto (WKY) rats.
- To examine the role of transforming growth factor beta 1 (TGF-β1) in VSMC growth regulation in hypertension.
- To assess platelet growth-promoting activity (GPA) in hypertensive and diabetic patients.
Main Methods:
- Comparative study of VSMC growth rates, contact inhibition, and cell cycle progression between SHR and WKY rats.
- Analysis of VSMC response to growth factors (e.g., EGF, PDGF, insulin, TGF-β1) and assessment of TGF-β1 expression and activation.
- Measurement of platelet GPA in patients with hypertension and diabetes, and evaluation of drug effects (e.g., HCTZ).
Main Results:
- SHR VSMC exhibited higher growth rates, abnormal contact inhibition, and hyperresponsiveness to growth factors compared to WKY VSMC.
- Augmented TGF-β1 expression and potential partial activation were observed in SHR VSMC, with TGF-β1 antisense oligodeoxynucleotide normalizing proliferation.
- Platelet GPA was elevated in hypertensive and diabetic patients; hydrochlorothiazide enhanced GPA in hypertensive patients.
Conclusions:
- Intrinsic growth anomalies in VSMC from hypertensive rats persist in culture, indicating a primary role in hypertension pathogenesis.
- TGF-β1 plays a significant role in regulating VSMC proliferation in hypertension, with potential for therapeutic targeting.
- Platelet function, specifically GPA, is dysregulated in hypertension and diabetes, and influenced by antihypertensive medications.
Abstract:
Inappropriate vascular smooth-muscle cell (VSMC) growth is the hallmark of vascular pathology in essential hypertension and diabetic macroangiopathy, whereas platelets constitute an important regulator of vessel wall homeostasis because of their content of various growth factors. Numerous abnormalities exist in platelet functions in diabetes and hypertension, such as enhanced activity and altered adhesion and aggregation. Increased thromboxane (TX2) production is characteristic of diabetes, and an elevation of intracellular free Ca2+ is found in platelets of hypertensive patients. By studying the growth patterns of VSMC from spontaneously hypertensive rats (SHRs) vs. those obtained from their normotensive counterparts, Wistar-Kyoto (WKY) rats, we have demonstrated that VSMC from SHRs exhibited a higher specific growth rate, abnormal contact inhibition, and accelerated entry into the S phase of the cell cycle. Moreover, they were hyperresponsive to many growth factors such as calf serum, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor beta 1 (TGF beta 1), and insulin. Additive effects were observed for EGF and PDGF or EGF and insulin. These intrinsic growth anomalies in cells of hypertensive origin persist in culture indicating their putative primary role in the pathogenesis of hypertension. Endogenous TGF beta 1 revealed an augmented expression of its message levels in SHR VSMC, the difference in mRNA between both strains being more pronounced at high cell density. Further, TGF beta 1 protein synthesis and secretion in VSMC culture were confirmed by immunoprecipitation of de novo labeled TGF beta 1. At high cell density, which most likely represents the physiological state of VSMC, plasmin, an activator of TGF beta 1, significantly stimulated DNA synthesis of VSMC in both strains. The reverse effect was obtained at low cell density. Yet, the fold stimulation was higher in WKY rats, suggesting that TGF beta 1 may be partially activated in SHR VSMC. This is supported by the inhibition of baseline DNA synthesis by TGF beta 1 neutralizing antibody in VSMC of hypertensive origin and not of normotensive controls. TGF beta 1 antisense oligodeoxynucleotide (ODN) nearly normalized the increased proliferation of SHR VSMC in culture. On the other hand, growth-promoting activity (GPA) in platelets of either diabetic or hypertensive patients was higher than in platelets of healthy controls and was found to be normalized by intensive insulin therapy in insulin-dependent diabetic patients. In hypertensive patients, however, hydrochlorothiazide (HCTZ)--even in low doses (25 mg/day)--enhanced the GPA in platelets, whereas other antihypertensive agents such as indapamide, atenolol, and captopril, had neutral effects.(ABSTRACT TRUNCATED AT 400 WORDS)